PHYSIOLOGYNEWS

summer 2004 | number 55

A publication of the Physiological Society Images of physiology Thelma Lovick takes a sideways look at neuroscience

Have you ever noticed how fashions change in physiology? How the most unlikely findings, once relegated to the ‘interesting’ phenomena file, suddenly become the latest thing? Or how Emancipation of astrocytes significant progress, sometimes made Then in the mid ‘80s, their time had in the late 19th or early 20th century, lies come. Between 1985 and 1990 there apparently dormant for decades? was a 500-fold increase in the annual rate of publications on astrocytes (data Such bits of information languish in from ISI Web of Science). These days dark recesses of the collective memory, you can hardly open a neuroscience using up space that could more journal without an astrocyte falling out. usefully(?) be dedicated to the really And they are so photogenic…quite cutting edge stuff. But then the beautiful and, thanks to modern image scientific climate changes and, enhancement software, they now come suddenly, yesterday’s worthy-but-dull in a huge range of attractive colours. fact gets re-examined, dusted off and catapulted to superstardom. One such Glial power candidate for superstar status has to be Now, astrocytes are recognised as the humble astrocyte. crucial participants in almost all of the integrated functions of the nervous Golgi and Cajal lit a slow- system. They clean, they feed, they burning fuse nurture, they repair. And who do they Where did it all start? Well, as with so do it for? It’s for those macho much in the brain, you will find that neurones. Behind every Cajal and Golgi had been there, stained successful/powerful neurone is a fleet it, named it and drawn a pretty accurate of astrocytes whose contribution has, picture - some 100 years or so until recently, gone largely previously. But the fuse they lit burned unrecognised. Are you surprised? You very slowly, at least in the shouldn’t be, it’s just a case of physiological consciousness. Astrocytes neuroscience imitating life. smouldered for a few decades…there were lots of them in the brain but they Thelma Lovick seemed very much back seat players. Outnumbering neurones by about 10 to one in man, they provided a supportive Send in your contributions for scaffold for neurones and generally ‘Images of physiology’. A £50 kept the extracellular environment tidy by mopping up excess potassium…and prize awaits the best image that seemed to be it. Because the real received for each issue of players in the brain were the neurones. Physiology News.

Far left, from the top: Cajal (left) and Golgi Astrocytes as seen by Cajal Cambrex online catalogue (www.cambrex.com) sfn.org brain briefings, December, 2000 (Vladimir Purpura) Nedergaard et al (2003). TINS, 26, 523-530 Left: Nedergaard et al (2003). TINS, 26, 523-530 PHYSIOLOGYNEWS Contents Editorial 3

The Society’s dog. ‘Rudolf Magnus gave Newcastle Meeting Barry Hirst 4 me to Charles Sherrington, who gave me Nottingham Meeting Paul Greenhaff, Michael Rennie 4 to Henry Dale, who gave me to the 6, 38, 40 Physiological Society in October 1942’ Images of Glasgow

Features Published quarterly by the Physiological Society The Athens Olympics: some lessons in thermal physiology Ron Maughan 5 That was the week that was ... Alan North 7 Contributions and Queries Executive Editor Halt on Cambridge primate centre Nancy Rothwell 11 Linda Rimmer From magnetic moments to medical imaging The Physiological Society Austin Elliott 12 Publications Office Can a single bout of exercise prevent decompression sickness? Ulrik Building 4A, The Michael Young Centre Wisløff, Russell S Richardson, Zeljko Dujic, Alf O Brubakk 16 Purbeck Road Cambridge CB2 2HP Understanding skeletal muscle hypertrophy: integration of cell signalling Douglas Bolster, Neil Kubica, Stephen Crozier, David Williamson, Peter Tel: +44 (0)1223 400180 Fax: +44 (0)1223 246858 Farrell, Scot Kimball, Leonard Jefferson 18 Email: [email protected] Bidirectional synaptic plasticity and motor learning in the cerebellum The Society web server: http://www.physoc.org Francis Crépel, Armelle Rancillac 20 Magazine Editorial Board The large conductance calcium-activated potassium channel (BKCa) and Editor Austin Elliott (University of Manchester) the ß2 adrenergic receptor (AR): a direct link to uterine relaxation Boonsri Members Chanrachakul, Fiona Broughton Pipkin, Raheela N Khan 22 Lesley Anson (Nature) Laura Blackburn (University of Cambridge) Imaging the activity of single calcium channels: ‘optical patch-clamp Munir Hussain (University of Liverpool) recording’ Angelo Demuro, Ian Parker 24 John Lee (Rotherham General Hospital) Thelma Lovick (University of Birmingham) Brain waves plainly speaking Yacov Fischer 27 Bill Winlow (Prime Medica, Knutsford) Getting insight into the work of tendons Oksana Kostyuk, Robert Brown 28 © 2004 The Physiological Society Vasopressin may limit its own secretion with the help of pituicytes Lia ISSN 1476-7996 Rosso, Brigitta Peteri-Brunbäck, Jean-Marc Mienville 30 The Society permits the single copying of Qualia and private languages Denis Noble 32 individual articles for private study or research. For copying or reproduction for any other purpose, written permission must be sought from the International News Physiological Society. Clinical physiology in Warsaw Bohdan Lewartowski, Andrzej Beresewicz 34 Why British physiologists should be part of the European Space Opinions expressed in articles and letters submitted Programme Michael J Rennie 35 by, or commissioned from Members, Affiliates or outside bodies are not necessarily those of the Council activities 10 Physiological Society. The Journal of Physiology 37

The Physiological Society is registered in England Affiliate News as a company limited by guarantee, UK Grad courses Laura Blackburn 38 No 323575. Registered office: PO Box 11319, London WC1X 8WQ Registered Charity No 39 211585. Letters to the Editor Society News Printed by The Lavenham Press Ltd Voices of the Future 2004 Emily Ferenczi, Andrew Murton 43 Deputy Executive Secretary on winning team Maggie Leggett 44 Cover photo The scanning electron Biosciences Federation Maggie Leggett 44 microscope image was Pfizer Prizes 45 generated by the Biomedical Unbelievable! 46 EM Unit of the University of Obituaries Newcastle-upon-Tyne and Gerald A Kerkut Robert J Walker 47 shows bovine rumen John Atherton Young Maynard Case 49 epithelium with adherent Graham Francis Baker Malcolm Segal, Richard Naftalin 49 microflora. This work was funded by a grant from Pfizer Nachman Ambache Desmond Greaves 50 Global Research to C. Hannelore Pawelzik Alex Thomson 50 Graham and N.L. Simmons Book Reviews 51 (School of Cell and Molecular Noticeboard 52 Biosciences) PHYSIOLOGYNEWS

Action points In this issue Grants Grant schemes have changed. For full information on Members’ and Affiliates’ Grants, Pfizer In Vivo Physiology Grants, Intercalated Welcome to the Summer issue. people into all sorts of occupations, as BSs Bursaries, Network Interaction Grants, Non- we hope you will see as the series Society Symposia Grants, Postgraduate Support One of the things we like to bring out develops. Fund information and the Vacation Studentship Scheme please visit: in Physiology News is the great http://www.physoc.org/grants variety of ways one can practise We are also committed to bringing experimental physiology, and the you news on issues relevant to Membership applications different places one can carry it out. physiologists. Apart from the regular Applications for Full and Affiliate Membership This time we have pieces relating to Society news, Nancy Rothwell are received throughout the year and have no deadlines. A decision is normally made within 10 physiology in Poland discusses the halt on the Cambridge weeks of the Administration Office receiving the (p. 34), in space (p. 35), under the Primate Centre (p. 11), while application. For full details please visit: sea (p. 16), in the searing heat (p. 5), young scientists Emily Ferenczi and http://www.physoc.org/join in the operating theatre and Andrew Murton report on anaesthetic recovery room room (p. meeting the parliamentarians, Change of address 39) and even in Birmingham (p. 40). including Secretary of State for Members should inform the Administration Office We have 20 pages of scientific articles Education Charles Clarke (p. 43). of any changes of address, telephone, fax or email address. and another 9 pages of features. Finally, several writers in this issue Changes can be emailed to: [email protected] or are worried about a traditional role of updated online at http://www.physoc.org Talking of features, in this issue we university physiologists, namely launch a new series: ‘A week in the teaching medical students (see pp. 23, life of ...’ Each issue a Society 40-41 and 46). Is this ‘service’ Physiology News member will tell us about his or her teaching undervalued? Or should we working week - we kick off with still be doing it at all? Deadlines Society President Alan North. In We are keen to hear what you, the Letters and articles and all other contributions for future issues we hope to use this Members, think. Let's keep inclusion in the Autumn 2004 issue, No. 56, series to bring home the full range of emailing and make the Physiology should reach the Publications Office ([email protected]) by 7 June, 2004. The what Members do with their working News letters column a real forum copy date for the Winter 2004 issue, No. 57, is 20 time – in Britain and abroad, in for discussion on this and any other September. Late copy can be included if space universities and other research issue you feel strongly about. permits. environments, and in other kinds of jobs. A training in physiology can take Austin Elliott Suggestions for articles Suggestions for future articles are welcome. Please contact either the Executive Editor or a member of the Editorial Group of Physiology News (see contents page for details).

Physiology News Online Physiology News is now available on our website: http://www.physoc.org.

Guidelines for contributors Length of articles References This will be determined by the subject matter Authors are requested to keep the number of These guidelines are intended to assist authors in and agreed between the contributor and the references to a minimum – preferably no more writing their contributions and to reduce the commissioning editor. Submission of articles than two or three. Please cite all references in subsequent editing process. The Editorial Group Authors should submit text in the form the style of The Journal of Physiology (see of Physiology News tries to ensure that all of a disk or emailed Word document, Instructions to Authors 2004 on the Society’s articles are written in a journalistic style so that to reduce the risk of introduction of errors website: they will have an immediate interest value for a during re-typing. wide readership and will be readable and http://www.physoc.org). comprehensible to non-experts. In particular, Illustrations and authors’ photographs scientific articles should give a good overview Authors are encouraged to submit diagrams, of a field rather than focus entirely on the drawings, photographs or other artwork to Submission deadlines authors’ own research. illustrate their articles or to suggest appropriate Please contact the Executive Editor in the illustrations. A photograph of the author(s) Publications Office (see Contents page for Format of articles should also accompany submissions. details) for submission deadlines. Submissions The main message or question posed Photographs may be colour or black and white, may be deferred to a subsequent issue, should be introduced in the first paragraph. The prints or transparencies or tif/jpeg files with a depending on available space. Short news items background for the topic should then be minimum resolution of 300 dpi. Electronic are encouraged and can usually be included as established, leading up to the final conclusion. colour figures should be saved in CMYK mode. late copy. EDITORIAL PN 3

Still on capturing the interest of future cranking out grant proposals or papers. Time to communicate? young scientists, it is clear that, for This brings me to a final critical point. secondary school children taking All the upbeat talk about scientists science subjects, television science needing to engage more with the public Most of us in science agree that better programmes in particular play an is great – but possibly over-optimistic. science education of the wider public is important role in getting them Let me pose a rhetorical question. a good thing. And the contemporary interested in studying biological Would a major UK research university view, coming from inter alia the top of sciences at university level. in 2004 rather an individual staff learned societies and research councils, member were writing a grant proprosal, is that this requires much greater Anyone who has interviewed a research paper, or a popular science ‘public engagement’ by the scientific prospective UK physiology book directed at a non-specialist community. But how, exactly, is this undergraduates over the last decade will audience? It is pretty clear the answer going to happen? Should learned have heard television series and would be the first preferred over the societies, like the Physiological Society, televised lectures given by people like second, and both of these heavily do more? If so, how? Should individual Colin Blakemore, Susan Greenfield and preferred over the third – although ‘all universities do more? Should individual Nancy Rothwell repeatedly mentioned three’ might be acceptable. Within the scientists, like Society Members and as one of the things that inspired them research community, the people who readers of this magazine, do more? to apply to do a physiology, or other have been most prominent in How? bioscience, degree. In this context it is communicating science to a wider worrying to hear that the Royal audience have tended to be highly Let’s start with the easy things. There is Institution Christmas Lecture Series is successful researchers who have no doubt that more science in the apparently under threat. somehow found the extra time to add public eye brings benefits, particularly communication to their other activities. in terms of getting children interested So what can the learned societies do? However, these people are clearly in studying science. As a child in the First, they are not idle now. The special in many ways, including their late 60s – and like, I suspect, many 40- Physiological Society organises an ability to deal with workloads way something scientists - I was totally annual workshop for the public (at the beyond the norm. One might suspect gripped by watching, and reading British Association Festival of Science), that there must be other people – about, the Apollo missions and moon produces booklets for schools, helps ordinary mortals? - within the science landings – perhaps one of the greatest support a database of scientists willing base who could contribute usefully to examples of an event, wholly based on to talk in schools, and organises several science communication, if they could science and engineering, which workshops a year for schoolchildren find the space and time. captured global public imagination. and one for teachers. It has also recently started issuing press releases. Perhaps the answer is to fund more Although the Human Genome Project But it is fair to say that it, and the other academic posts specifically in Science and the discovery of human stem cells similar societies, could probably do Communication, or Public are undoubtedly epochal scientific more. Understanding of Science. Perhaps events, they have yet to find their universities could second lecturing staff public ‘hook’ – their equivalent of At the individual level, what can from their ‘normal’ activities to ‘public putting a man in space, or on the moon. Members do? Many universities now science communication duties’ for part run schemes for staff to go to local of their time. Research Councils and The importance of using opportunities schools and discuss science and other funding agencies could offer more like those presented by ‘experiments in scientific issues with children – public grants targeted at efforts in science orbit’ to get young people turned on to engagement at the grass roots. communication, or fellowships to biological sciences is something that However, this inevitably takes time and enable staff time to be purchased for Mike Rennie emphasises in his article effort. Some research scientists describe this kind of work. The danger is that, about the European Space Programme their work for publications aimed at a without a continuing commitment to on p. 35 of this issue. One suspects that general audience, or at specific target imaginative solutions of this kind – and something happening now, like the groups such as 6th form science without investment of real money to Beagle 2 project, speaks to the public students. Sadly, any exposure raises support them – all the good intentions far more than the airy promises of inevitable issues regarding animal in the world are not going to deliver future cures from genome-based rights protests for those who ‘go more public engagement from ever- research. There is also the danger that public’. But – and, I suspect, more harder-pressed science researchers and too much talking up the future causes universally – there is also the problem teachers. cynicism when delivery is slow; gene that writing ‘popular’ articles takes time therapy for cystic fibrosis, anyone? that could otherwise be spent Austin Elliott 4 PN MEETINGS

Nottingham Meeting Responsiveness of muscle, bone and connective tissue to physical activity: genetic and molecular integration

A Physiological Society Focused the linking of changes in muscle The Meeting will take place at Meeting of the Human Physiology myofilament turnover with the turnover Nottingham University Medical School Special Interest Group will take place of extracellular matrix, the marked in Derby, which has brand new state of at Nottingham University Medical response of tendon to exercise, and the the art audio-visual facilities and School in Derby on 12-13 July, 2004. existence of genetic traits which make lecture theatres. Accommodation will human beings good or poor responders be within easy walking distance of the The application of modern techniques to exercise. meeting, a Society dinner will take of physiological, pathophysiological place at the Meeting and plans are in and post genomic technology is This Focused Meeting of the Society place to run a social programme in providing us with unforeseen will allow the latest physiological tandem with the Meeting. Attendance knowledge concerning the way in findings to be set in a context of will be limited to 100 delegates on a which the musculoskeletal mass, which transcriptional and translational control first come first served basis. comprises 80% of our lean tissue mass, of the tissues of the musculoskeletal Programme and registration details will maintains itself and adapts to differing system some of which, like bone and be available at: degrees of physical activity and tendon, were hitherto thought only to http://meetings.physoc.org/ changing environments. Some respond weakly and slowly. remarkable physiological phenomena Furthermore, the programme will Paul Greenhaff have been discovered, e.g. the marked include oral communication and poster Michael Rennie anabolic response of bone to vibration, presentations by attendees. University of Nottingham

Newcastle Meeting Epithelial-bacterial pathogen interactions

A Physiological Society Focused Gadi Frankel, Martin Kagnoff, Brendan Meeting will take place at the Kenny, Nicholas Mantis, Andre University of Newcastle-upon-Tyne Ouellette and Andrea Varro will speak on 22-23 July, 2004. at the second symposium (Epithelial- bacterial pathogen interactions: This highly Focused Meeting will subversion of physiological processes consist of two related symposia, in the gut), organised by Barry Hirst discussing the interactions of human and Anjam Khan. pathogens with respiratory and intestinal epithelia. The aim will be to Free communications and posters will highlight recent developments in our be presented during the Meeting understanding of how bacteria interact following Physiological Society and modulate the physiological guidelines. Registration, which is function of these epithelial barriers, at necessary to attend, is free to Society the molecular, cellular and whole tissue Members and members of the level. University of Newcastle-upon-Tyne and will be available at: Speakers at the first of the two http://meetings.physoc.org/ symposia (Epithelial-bacterial pathogen interactions: new insights into host Further information is also available response to acute and chronic lung from the University of Newcastle- infections. Who is talking to who?) upon-Tyne website at: will include Brad Britigan, Gerd http://www.ncl.ac.uk/camb/research/EBPI/ Doering, Ed Galyov, Peter Greenberg index.htm and Florian Lang. This symposium is organised by Mike Gray and Phillip Barry Hirst Aldridge. University of Newcastle-upon-Tyne FEATURES PN 5

The Athens Olympics: some lessons in thermal physiology Ron Maughan continues our series of articles on exercise physiology in the run up to the summer Games

Every few years a major sporting event critical level of core temperature, takes place in an environment that perhaps due to temperature reducing poses special challenges to the motivation.’ She proposed that participants. It may be altitude, cold or attainment of a critical core temperature air pollution but, more often, it is heat would inevitably result in fatigue, as a that causes the biggest problems. Over protective mechanism against thermal the years, there have been many injury. At the time, objections to examples of spectacular collapses in Nielsen’s Critical Core Temperature marathon races, including the examples Hypothesis were raised, in particular of Dorando Pietri, who collapsed on the the failure to provide a plausible track close to the finish of the 1908 biological mechanism for this Olympic Marathon in London, Jim phenomenon. There was also no Peters, who fell to the track in the evidence of a specific core temperature Empire Games Marathon in Vancouver at which fatigue ensued. However, the in 1954, and many other less high typical measure of core temperature in profile problems. These problems are Fluid intake is important in maintaining cardiovascular exercise physiology studies is rectal seldom seen when competition takes function and thermal homeostasis, and athletes will temperature, and no-one would believe place in cool environments – although look at optimising their hydration strategies that the rectum is the site of fatigue. athletes still experience extreme fatigue which may be about 5-15ºC. At the Since then, however, animal studies – and they are most often seen in point of fatigue in exercise in the heat, have provided evidence that there is a events lasting an hour or more. the muscle glycogen content remains critical level of brain temperature high, so substrate availability seems not beyond which animals will not continue In my days as a physiology student, to be limiting. There is also compelling to exercise voluntarily. The there was an ongoing debate as to evidence that raising body temperature Copenhagen group have applied this to whether the limitation to exercise prior to exercise can impair man, providing compelling evidence for performance lay in the cardiovascular performance, while pre-exercise a thermal limitation to performance: system or in the active muscles. The re- cooling can improve performance. cerebral heat exchange was measured introduction of the needle biopsy These manipulations have little or no in exercising subjects by continuous technique for sampling skeletal muscle effect on the pattern of substrate use in monitoring of aortic and internal provided compelling evidence that skeletal muscle. jugular vein temperatures during fatigue in prolonged exercise – at least exercise. They found that brain in cycling, but less convincingly so in In 1993, Bodil Nielsen wrote in The temperature is higher than core running – was a consequence of Journal of Physiology that ‘Physical (arterial) temperature. At high ambient depletion of the muscle glycogen store. endurance in hot, dry environments temperature, heat loss is reduced, so When carbohydrate is not available to appears to be limited by attainment of a brain temperature rises much faster. the muscles at a rate sufficient to allow the rate of ATP resynthesis to match the rate of hydrolysis, then the energy demand – the speed of running or cycling – must drop to a point where it can be met by fat oxidation. Even in trained athletes, the maximum rate of ATP resynthesis that can be achieved by fat oxidation is only about 50% of that from carbohydrate oxidation.

However, several lines of evidence now suggest that this is irrelevant when exercise takes place in a warm environment. Exercise capacity – measured as the time for which a fixed speed can be sustained – is reduced progressively as the temperature increases above an optimum level, Over the years, there have been many examples of spectacular collapses in marathon races 6 PN FEATURES

They have also shown an altered EEG skin temperature to maintain the vapour excellent textbook published in 1919, pattern in hyperthermia consistent with pressure gradient that drives Bainbridge (he of reflex fame) was able changes in motor neuron activation evaporative heat loss. To maintain a to write that ‘It has long been thresholds and increased perception of high skin temperature, however, recognised that the main seat of fatigue fatigue. In a further study, they showed requires a high skin blood flow, and a after muscular exercise is the central reduced force generating capacity in falling cardiac output does not permit nervous system. Mosso long ago stated individual muscle groups when core this. that ‘nervous fatigue is the temperature was high. Further support preponderating phenomenon and for a link between a hot brain and Various strategies are available to the muscular fatigue is also at bottom an fatigue comes from an abstract athlete to help cope with the conditions exhaustion of the nervous system.There presented at last year’s annual meeting anticipated in Athens. Prior heat appear, however, to be two types of of the American College of Sports acclimation improves sweating fatigue, one arising entirely within the Medicine. Subjects were exposed to responses and there is some evidence central nervous system, the other in passive heating by a water perfused that it also lowers pre-exercise core which fatigue of the muscles suit, and the MVC of the knee extensor temperature. Fluid intake is important themselves is superadded to that of the muscles was measured. Muscle in maintaining cardiovascular function nervous system’. That sounds like a activation was assessed by the twitch and thermal homeostasis, and athletes pretty good description of the current interpolation technique. Activation will look at optimising their hydration state of thinking. decreased from 80±10% at baseline to strategies. Pre-exercise cooling, and 65±11% when rectal temperature cooling between successive rounds of Ron Maughan reached 38.5°C. competition, will be employed by School of Sport and Exercise Sciences, Loughborough some. How effective these strategies University, Loughborough, UK The rise in core temperature during are will have some bearing on who exercise in the heat is limited by wins the gold medal in some events. evaporative heat loss, but this has two In the next issue Mike Gleeson writes consequences. Fluid loss as a Although we now understand much on training and competition stress: consequence of sweating impairs more about the thermal limitations to effects on immune function and health cardiovascular function, and cardiac exercise performance than we did a few and Henning Wackerhage and Phil output falls. Maintenance of a high rate years ago, there are still important Atherton explain adaptations to of evaporative heat loss requires a high lessons from the older literature. In an marathon training

Images of Glasgow Clockwise from top, left: A man and his toys - David Eisner, complete with laptop, PDA, mobile phone AND camera!; This imposing biological exhibit stands guard outside the Hunterian Museum (we don’t know if he supports Celtic or Rangers); The Hunterian Museum and other nearby Glasgow University buildings give the Meeting site a very Victorian Gothic feel; The hot seat - this chair contains a black stone on which Glasgow University students were required to sit for their Oral Examinations. This was the practise from the beginning of Glasgow University until the mid- 19th century. Note the hourglass, presumably for timing the examination; Godfrey Smith with symposium speakers Jon Lederer (left) and Guy Salama.

(Photographs by Austin Elliott) See p. 38 for Glasgow: art and culture A WEEK IN THE LIFE OF PN 7

That was the week that was… No week is typical for Alan North, so he chose this one, when magazine Editor Austin Elliott finally persuaded him to move the piece up his mind's agenda and onto paper…

Sunday of Manchester. And probably, I This day begins in the lounge at discover, it will necessitate an early trip Heathrow airport, reading my email. I to Korea. am returning from a very brief meeting in Minneapolis, advising a small Hye-Youn, a research assistant carrying company starting up in the pain area. I out RT-PCR on lung ion channels, tells admire the entrepreneurs who will turn me that our stored human lung science into medicines, in this or any macrophage RNA has partially other area, but after another British degraded after some months in the Airways night I am wondering how freezer. This project forms part of a long I can keep up this particular kind collaboration with AstraZeneca and is of long distance support. Among the run by a senior postdoctoral colleague email correspondence: Maynard Case Amanda Mackenzie: we get together to has some pieces relating to my re-prioritize our study of some impending move to Manchester; David remaining channels. The choice is Brown is giving information on the up- made more problematic by the coming St Petersburg meeting on realisation that the departmental Figure 1. Alan North, current President of the membrane transport – and also Physiological Society fluorescence-activated cell sorter is no responding to my suggestion to hold a longer available (the technician recently symposium to honour the recently CD. Sadly, I now realise that my quit), making it difficult to isolate a deceased autonomic physiologist mobile phone, which I had noticed further supply of cells. It is the modern Vladimir Skok – and, no surprise, a missing at Manchester airport on way of science, which requires a long request to review a manuscript from Thursday, was not plugged into the term management effort to coordinate one of the Senior Editors of The charger in my office – the one place the participation of surgeons, other Journal of Physiology. that I thought I was most likely to find academic colleagues, FACS it. I had felt rather naked without it in technicians, and electrophysiologists. On the plane up to Manchester, I work the US – funny how these recent Then suddenly one link in the chain some more on the further drafting of a technologies so quickly become breaks. A different form of physiology paper destined for J Gen Physiol that essentials. from my early days – take an animal deals with the channel vs pore features and start the experiment in the morning, of the P2X7 receptor. Like many of my Monday and continue until the cells or the recent papers, this one was easily I am in the office soon after eight, preparation faded in the evening (or conceived, but has been too many which is about usual, having dropped early the next morning!). months in gestation. It is getting close, off my 11 year old son at his school though some aspects need to be played close to the University. Adrian prefers Jessica tells me about the missing down a bit and a couple of figures re- the croissants that are available there to phone -- the bad news is that it is not in jigged. I feel that the paper needs a the breakfast that I might prepare! any of the obvious places where I quantitative model to illustrate the There is not a lot of activity in the might have left it, but the good news is conclusions; I started on it some laboratory at that time of day, but my that nobody has put thousands of months ago but am doubtful now that I assistant Jessica Hinchliffe soon pounds worth of calls on it over the will ever find the time to finish it. arrives. Even before she has taken off weekend. There would normally have her coat I beseech her to help been a few phone calls to make on my I currently serve as Chair of the MRC retrieve/cancel/replace my phone! She journey down to London, although Cross Board panel and there is a is unflappable – it will be done. A new unlike most of my fellow travellers I briefing meeting scheduled for Monday meeting has appeared in the calendar have a distinct aversion to discussing at 3.30 pm. But when I get home to for 9.00 am. This is with a colleague any kind of business in railway Sheffield I realise that the final set of (Kei Cho), with whom I am organising carriages. So I find some fortuitous papers (the referees’ comments) arrived a substantive collaboration with the peace in that regard, and have the at my office only on the Friday, so I Brain Research Centre in Seoul. It is a chance for a final read through the have to go into my office at the joint venture with neuroscientists in referees' reports for the 44 MRC grants University to pick them up. Not too Bristol and Sheffield, and needs some – they are easy to go through on a lap- bad, the pile of papers is only three urgent discussion in the light of my top. The meeting at 3.30 pm is with the inches high, and luckily it is also on forthcoming transfer to the University MRC staff responsible for the grant 8 PN A WEEK IN THE LIFE OF applications. It gives us the opportunity to highlight any particular areas of concern, so that we can alert primary reviewers if necessary in the two days prior to the review meeting itself.

That evening is a pleasant event in which I join about 20 others for dinner at a small Italian restaurant in the Lambeth area – they are the Council of the Physiological Society. Some say, indeed some Council members say, that Figure 2. Tribute to mentors. Gordon Lees, Syogoro Nishi, Hans Kosterlitz (left to right). Syogoro Nishi is an the events are a boondoggle, and an honorary member of The Physiological Society, Gordon Lees an honorary member of the British Pharmacological unnecessary expense. In fact, I spend Society, and the late Hans Kosterlitz was an honorary member of both societies. the meeting in conversation with Giovanni Mann and Maggie Leggett Rennie with respect to the Mars meeting – the journey is not atypical discussing possible new ways to mission in 2031! (service first delayed and then support younger physiologists, and cancelled at Luton and the entire train particularly how to involve physiology I bring the meeting to a close at 11.45 contents disgorged onto an adjacent undergraduates and PhD students in am and, after a quick sandwich with train). On the other hand, one journey school visits. The food and wine do Council members, I take a cab over to from London to Sheffield last year that 'enable' such discussions, and I feel that the London offices of Nature should have been a 2 h 10 min direct they are a useful adjunct to the formal Publishing Group. They publish the service involved me travelling on four meetings of Council. British Journal of Pharmacology (BJP), different trains and arriving 3 h late, so Tuesday of which I am currently Editor-in- all things are relative. The loss of my The London hotel is not too luxurious Chief. At the meeting are two of our phone prevented me from telling Mark and some Council members can find no Senior Editors, the journal manager, of my delay. But the train journey seat for breakfast; those of us who do, Nature Publishing Group staff and an allowed me to make a start on this continue much of the previous outside consultant. On the agenda there article... evening's conversations. It is a 20 is a new meeting that is being planned minute walk over to Guy's for the to promote the BJP, very much After some time spent poring over meeting itself and its 9.30 am start. modelled on The Journal of Physiology future floor plans I leave the laboratory One of the most significant agenda symposia that have been held around around 7.00 pm. This was good timing items is the provision of substantial the world in the past few years. This to pick up my son from his football funds to rectify a pension shortfall for time the topic is ‘Pharmacology of the practice, and get home to watch the some of the Society's staff. The Lower Urinary Tract’, planned for game between Arsenal and Celta Vigo Executive had previously considered December 2005 in association with a with him. And, as the day was Shrove this at length, and of course taken meeting of the Scientific Branch of the Tuesday, the half-time interval allows professional advice. Nonetheless, it is American Urological Association me to cook the traditional pancake fare. good to see significant Council (SBUR). These things need a good In this part of the world these are thin discussion with many members taking head start – in this case the crêpes served slightly crisped with part, which ultimately led to a revised arrangements are potentially complex, sugar and lemon juice: they are most decision which all considered fair. involving NPG, BJP and the SBUR. often eaten for breakfast, but evening We discuss the outline of a joint serves equally well! There are other key items: a bid to host contract, and the urgent need for a the 2013 International Union of provisional business plan to get the Wednesday Physiological Sciences congress must project off the ground. A day in the laboratory, with few be prepared by the end of September. appointments. Still a lot of reading to And, talk about forward planning, a Back in Sheffield at 5.00 pm I have a do in preparation for the panel meeting small budget was approved for meeting scheduled with Mark Dunne. at the MRC tomorrow. The day starts lobbying efforts to place physiological Mark was, until recently, the Society’s with a session with Jessica, which sciences in the funding picture with Meetings Secretary. He is head of the brings the urgent realisation that the respect to the Aurora manned mission Division of Physiology, Pharmacology date of the next meeting that I had to Mars scheduled for 2031. Whereas and Toxicology in Manchester, and this proudly announced to the Physiological Meetings Secretary Bridget Lumb meeting has to do with space and Society Council yesterday was the apologised that she would not be facilities in Manchester when I move wrong one. I am a slow learner, but holding her post in 2013, there was no there in July. Thanks to Midland now I have at last figured out that my such humility on the part of Mike Mainline I arrive 30 min late for the calendar is best left entirely to A WEEK IN THE LIFE OF PN 9 somebody else. Jessica calls David before it's time to fix dinner. process. This is the penultimate Sewell and we send out an immediate My wife Annmarie Surprenant (who is meeting of the Cross Board Group, correction and abject apology. also a professor in the Institute of which is destined to be replaced in the Molecular Physiology at the University summer of 2004 in the new portfolio of A third year undergraduate student of Sheffield) has spent the latter part of MRC grants recently announced. The comes to see me about his library the day visiting AstraZeneca, with meeting finishes at 4.00 pm after a final project on P2X3 receptors and pain. I whom she holds a research reflective view of the outcomes, aided was most impressed at the list of a collaboration. She is enthused about in this modern age by a projected dozen or so papers that he had prepared the possibility of perhaps, at long last, display of a spread-sheet on a large for discussion, including a very recent being able to publish some of the work screen. I like this system because it is review by R A North in The Journal of that has been carried out with their fully transparent, and gives all the

Physiology entitled ‘P2X3 receptors and compounds; in fact they have turned Board members the opportunity to re- pain’. Seems like one student on his out to be good tools with which to open discussion, or to revise or refine way to a First Class degree! probe physiological function, and the their assessments of the grants scientific community needs them in the considered for support. Most At 12.30 pm the informal ‘journal club’ public domain. She was less importantly, it allows the entire group takes place; this is a 10-15 min enthusiastic about the earlier part of the explicitly to take responsibility for the whiteboard presentation by someone in day, which saw her taking an collective decision. the lab of a recent paper. The event has examination set by the Home Office. been running daily at 12.30 pm in my Nonetheless, she had some entertaining The 4.00 pm finish allows me time to laboratory for about 25 years, with stories –such as one of her biochemical visit Waterstone's down by University many stops and starts, and survives colleagues who had asserted in College before meeting my 19 year old because of its essential informality response to one question that the son Chris. I am looking for a book by (which is another way of saying that typical weight of an adult laboratory rat Donald Kennedy, a scion of American you don't come to listen if you have was 1 kg. academic life who is now Editor-in- something more important to do, like Chief of Science. Chris is a student at an experiment, and you don't come to Thursday the Guildhall School of Music, present if you are lazy, fearful or Today is a 6.00 am start, and I am into specialising in Composition. We find a uninspired). The presenters rotate London soon after 9.00 am. The two nice restaurant on Charlotte Street and through all laboratory members – hour train ride allows the final after another beer or two I finish up professors to PhD students; today it is preparation for the Cross Board running for the 9.25 pm train from St one of my own graduate students. meeting. The MRC Council room is Pancras. This means home around filled today, no apologies received. The midnight. Half an hour with another member of 20 members of the Board are drawn staff dissecting and discussing a paper from all areas of medical science, Friday prepared for submission that I had read ranging from clinical trials and public The morning begins with a 9.00 am on the last US trip. Half an hour spent health to protein structure. They have a laboratory meeting. I hold joint writing a letter of reference for an tough task, reviewing grants that are laboratory meetings with Annmarie. appointee to an overseas professorship. sometimes distant to their expertise, but Today one of her group is talking – Two hours reviewing overdue aided with several expert referees' Richard Varcoe is a Wellcome Trust manuscripts for The Journal of reports. Some grants reach early Clinical Research Fellow studying the

Physiology and other journals. consensus in minutes, other require role of P2X7 receptors in endothelial discussion for an hour. The meeting is cell function. He has become the And then home around 4.00 pm business-like and forthright, and I am resident expert on quantitative RT-PCR because that's where the MRC grants once more impressed by the care and and, as usual, I learn a lot from his are (the 12 inch pile) for tomorrow's fairness with which these Board presentation. meeting. I put another 3 h into them members contribute to the peer review The meeting is followed by an appointment with a visitor who wishes to discuss the possibility of a position in Manchester, and then by a meeting with Liz Seward, another staff member in the Institute of Molecular Physiology. Liz and I are jointly supervising a new PhD student and we sit with him together to look over his recordings of ATP-induced currents Figure 3. Tribute to the alma mater. The University of Aberdeen has awarded Alan BSc (physiology), MB ChB from PC12 cells transfected to express (medicine), PhD (pharmacology) and (illustrated here) hononary DSc degrees. P2X receptors. It is known that these 10 PN A WEEK IN THE LIFE OF/COUNCIL cells have a native channel that is very nearby ‘edges’ – the rocky gritstone likely homomeric P2X2, and the student cliffs that border many of the nearby Council activities has found that this can be readily moors. The great attraction of life in suppressed by transfection of a Sheffield is undoubtedly the proximity The agenda for the February meeting

‘dominant-negative’ P2X2 subunit to the Peak district with its wealth of of Council included future IUPS carrying a point mutation in its ATP walks through open country. Often on meetings, the Aurora mission to Mars binding site. We are trying to devise a weekend morning I run along the cliff and the follow up to the strategy experiments that will allow us to use top trails. These are the same gritstone discussions held at the last meeting. this finding to determine the normal crags that influenced my teenage years, The Council agreed that a bid should trafficking cycle of the native subunits. and turned me towards a life that for be made to host the IUPS meeting in many years involved exploring the 2013. Hosting such a meeting is quite But at 11.30 am a taxi is waiting. Off world’s distant mountain ranges. This an undertaking, as the venue would to Manchester again. I have taken a love of mountains was an important need to hold at least 4000 delegates. new position there as Vice-President reason for studying medicine, since a However, it will fit well with the new and Dean of the Faculty of Life medical degree is a ready passport to policy of having one main meeting a Sciences. Although it does not start expedition climbing. My interest in year, and we are grateful to the until 1 July 2004, the merger of the physiology developed as an out-growth Meetings Secretary, Bridget Lumb, for University with UMIST has thrown up of the medical curriculum, driven coordinating the working party which some issues that cannot wait. Today it primarily by my frustration at the lack will draft the proposal. is the appointment of Associate Deans of quantitative thinking in biology but for Research and for Teaching. The also influenced by a fortunate Mike Rennie brought the attention of meetings are billed as 'interviews', a interaction with Hans Kosterlitz who the Council to the lack of bioscience notion that I rather dislike. I see it was one of my physiology teachers in input into the Aurora Mission to Mars. more as a dialogue to try to persuade Aberdeen (before he became Head of He suggested that a significant the best people to give up some of their Pharmacology). lobbying effort should be directed to research time to help with the make research councils and So, instead of running and walking over substantial administrative load imposed government aware of the need for the moors today I head into the largely by outside (i.e. government) physiological research before the laboratory for a few hours to finish off forces. This reminds me how mission. He offered to take the lead on the revisions of another manuscript. antediluvian I find the whole procedure this, which the Council gratefully This one is a re-submission for the for recruiting academic staff in UK accepted. British Journal of Pharmacology; after institutions. I have been thoroughly 2 months of further experiments we influenced by my 18 years in US At the Council meeting last November hope that it might now be acceptable. academia, and find mildly absurd the strategy break out groups discussed, No special dispensations for Editors-in- notion that people are being considered among other things, relationships with Chief. in competition for posts with the societies overseas. At the February meeting the Society’s president Alan pathetic salaries and the meagre The only other person in the laboratory North reported that he has initiated facilities generally on offer in the UK. this Saturday afternoon is our American contact with John Williams, Chairman Choosing one's colleagues is by far the visitor Jim Galligan. He is an of the American Physiological Society. single most important aspect of the autonomic physiologist with substantial I will keep you updated with progress professional life of any senior programmes back home in in this area. academic: it can only be done by a gastrointestinal motility and the series of one-on-one meetings to innervation of veins, and some years Some of the rest of the meeting was identify the best candidate and then ago he identified ATP as a transmitter devoted to housekeeping issues, providing him or her with every between neurons in the wall of the including the move of the London possible reason to join. It cannot be intestine. In Sheffield he is recording office at the end of April. I trust the done by a 40 minute revolving door currents through P2X receptors administration staff will be happy in series of interviews. expressed in HEK cells, and happy with their new accommodation, the address the ability to be able to do experiments By the time the meeting ends I have no for which can be found on the website. undisturbed at the weekend. I drop him time for the planned beer with a few of off on my way home at around 6.00 my future colleagues before journeying Dafydd Walters pm. He’s coming over to our house for home. The good news here is that the Chairman of the Executive Committee dinner tomorrow evening, which means train stops in Dore before reaching I’d better stop by the grocery/liquor Sheffield; by alighting here I can take a store... but then tomorrow is another 10 min walk and arrive home at 7 pm. week. Saturday The snow covered ground dissuades me Alan North President, The Physiological Society from the ideas of a run along one of the FEATURES PN 11

Halt on Cambridge primate centre Nancy Rothwell considers what it means for the future of UK research

ambitious to plan a stand-alone primate the University. The current facility, and it may be helpful to government, and our Minister for develop such facilities close to smaller Science in particular, has been units in the research laboratories outspoken in its support for biomedical involved – though in many cases this research and for the need to use will attract significant additional costs animals. They now need to ensure that for management and welfare support. legislation is in place and is fully ‘We need to be more active to the violent actions of a implemented to prevent the harassment small number of protestors’ - Nancy Rothwell Recent MORI polls suggest that the of anyone linked with such research. vast majority of the British public Even when violence is not used, supports animal experiments – provided continual threats to scientists, their rigorous controls are in place. A recent families, their friends and their The proposed new primate centre at BBC poll attracted over 400,000 votes neighbours are extremely disturbing. Cambridge University has attracted and found that 93% supported the use much publicity. The Deputy Prime of animals in biomedical research. So But the government and the law alone Minister granted planning permission, how can a major research facility be cannot solve this problem. The in spite of protests from animal rights halted in its tracks? The protests scientific community has a role and a groups, and the basic funding was in against Huntington Life Sciences (HLS, responsibility. For understandable place through the award of a JIF bid. the contract research company located reasons, only a handful of scientists But the University of Cambridge quite close to Cambridge) have featured speak or write publicly about animal decided, after considerable heavily in the news. SHAC (Stop research. Knowing the huge public deliberations, not to go ahead. Their Huntington Animal Cruelty) has support from many recent polls decision is understandable. Aside from mounted an extensive and sustained (completely verified by my own the significant increase in capital costs, campaign to close HLS, involving extensive experience of talking to the University had to think about the threatening, abusive and sometimes children and the public about such ongoing security costs and the violent behaviour, not only towards issues), we must all participate more. implications of continuing protests for HLS employees, but also against its We are unlikely to change the opinions the University and its neighbours. This investors and customers. Thanks to the of extremists, but by gaining the was probably an inevitable decision, resilience of its staff and strong support of a large proportion of UK but a very sad one, not only for British government support, HLS remains open society we can win the argument. research but also for democracy. and SHAC appears to have failed in its bid to close the company and in gaining This article was written on a British There is no doubt that primates, as our widespread public support. Council visit to India. I was surprised nearest relatives in the animal kingdom, when they asked me to talk about elicit great concern when they are used But a new organisation, Stop Primate experiments on animals and for biomedical experiments. That Experiments at Cambridge (SPEAC), antivivisection groups. This is a small concern is shared by the public and by which probably includes many of the but growing problem in India where many scientists, including myself. For members or supporters of SHAC, has many animals are held sacred. My these reasons legislation on the use of found a new target – the proposed message was that the solution is largely primates is the most stringent. Some Cambridge primate centre. Unlike in the hands of the scientific research simply cannot move forward companies, universities cannot mount community who should devote some of without the use of a small number of extensive security because they are their precious time to public primates. It is this type of research open places of teaching and learning communication. which is being considered in for thousands of students. The vast Cambridge – peer-reviewed, considered majority of members (staff and Avoiding repetition of the unfortunate carefully by local ethical review, and students) of any university will have events in Cambridge is also partly in which would benefit, like the animals it little in-depth knowledge of how and our hands. We need to be more active requires, from a new facility. The why animal experiments are conducted rather than responsive or even passive University of Cambridge cannot and of the strict legislation in place. to the violent actions of a small number endanger its staff and students, cause of protestors. disruption to local inhabitants or deploy The questions now are what does this excessive police time, let alone meet mean for Cambridge, for animal Nancy Rothwell the extra projected costs which would research in other universities and for MRC Professor, University of Manchester and inevitably detract from other important UK science in general? SPEAC/SHAC Chairman, Biosciences Federation Animal Science research projects. Perhaps it was have claimed victory and a new target – Group 12 PN NOBEL PRIZE INTERVIEW

From magnetic moments to medical imaging Austin Elliott talks with Paul Lauterbur, American chemist and joint winner of the Nobel Prize for Physiology or Medicine, 2003 for his work on magnetic resonance imaging (MRI)

Austin Elliott (AE) Did you and pathologists, but I thought [that] was [British Laureate] Peter Mansfield likely to be much more characteristic of actually do some of the work together? infiltration by tumour cells in detail In Britain it was implied in some news than a broad overall number that stories that you did. referred to the condition of a piece of tissue. Paul Lauterbur (PL) No, that’s not true. At one time it was very useful [So] I was observing these experiments, to visit Nottingham, not only because which were somewhat tricky and Peter Mansfield was there - who I difficult technically because they relied could talk to a little, but we never upon [a kind of NMR technique which worked together - but Raymond Paul Lauterbur and his wife, the physiologist Joan was] notoriously susceptible to artefacts Andrew* was also there, [although] he Dawson, pictured in London in December 2003 en of various sorts. There was a laboratory was a rather high and mighty professor route to the Nobel Ceremony in Stockholm. Both have worked at the University of Illinois in Urbana since that had done earlier work on behalf of and dean who did not talk to mere 1985. Paul Lauterbur was previously at SUNY Stony Dr [Raymond] Damadian and I was not mortals in general. Brook, while Joan Dawson was Lecturer in Physiology at all sure whether the numbers were at UCL where she worked on muscle metabolism (using P-31 NMR) together with the late Doug Wilkie. valid - not because of the people The only intense interaction I had with involved but because the techniques Peter Mansfield was when we were involved were those I knew easily gave trying to arrange a fellowship for a AE That’s what I had always a source of errors. When I observed junior member of the Department. I thought – that you were two people these experiments in person [and] saw had to carry out the negotiations working independently, but towards the results on the machine, I also saw between Raymond Andrew and Peter, similar ends. there were large differences in the who did not get along well, but worked signals from various tissues as well as in the same department. So I went PL His ideas came more from his those from pathological conditions. from Peter’s office to another part of work on complex pulse sequences to do And I was thinking that it would be the building to talk to Raymond and [NMR] spectroscopic work on solids much more promising to follow up on then tried to negotiate back and forth, and mine came from work on ordinary such work if it could be done by taking which at the time I likened to high resolution NMR. [Our work] measurements within a living animal or negotiations between Israel and Egypt. partly converged later but was quite human being instead of on locally cut- AE So when did you first become different then. up samples. While thinking about that aware of Peter Mansfield and his work in the evening of that first day, I then, just through reading papers? AE What did you actually start out realised there was something in trying to do, as opposed to what you principle that would enable you to PL I heard that he had made some ended up doing? perhaps achieve that end. But there sort of a presentation, in Tallinn in were many questions to be asked and Estonia, late in 1973, from a colleague PL The incentive to develop the answered, and so I thought it was a who had been at a physics meeting ideas [came from] witnessing some very promising insight but didn’t know there. It was reported that [Peter studies of rat tumours by a group from that it could actually be a technique yet. Mansfield’s work] was similar to mine, Johns Hopkins University. They were And then it occurred to me that there but it was clear Peter had never read doing something which didn’t bother was a chance that it could be made into my paper – he doesn’t read the them at all - sacrificing rats and cutting a practical technique. contemporary literature in any case, and out little pieces of various tissues –and was very shocked and surprised that there was speculation going around that AE That almost counts as a kind there was something similar in press! this sort of thing could be used to of ‘Eureka’ moment. It was clear from reading Peter’s first characterise tissue, particularly papers that [his work] came from malignant tissue. As a mere chemist I PL That moment was over dinner completely different sources than mine, thought it rather strange that people that night, having a hamburger in a so they were truly independent ideas in would envisage a medical procedure in local fast food restaurant with a friend. that sense. which to diagnose your problem they I did suddenly realise that there was the would cut you up. I was a little bit beginning of an idea that might be aware that something like that was developed into something useful. Not * E Raymond Andrew FRS (1921-2001), NMR Pioneer and done with biopsy samples and that no-one else had ever used magnetic Professor of Physics in Nottingham 1964-1983 microscopic characterisation by field gradients before in a one- NOBEL PRIZE INTERVIEW PN 13 dimensional way, very specific to the themselves, rather than writing down speaker was very flattered to see [particular] experiment and with no things as a permanent record for someone sitting in the audience looking intimation of generality in the process. history. up at the board occasionally and But from the very beginning I was vigorously writing on a pad of paper, thinking of it as a general process, AE In England now people debate but he didn’t know what I was writing actually. Although the citations often a lot whether you can get funded for an – nothing to do with the seminar! refer to two-dimensional [imaging], that idea for a technique as opposed to was a more practical way than the solving a scientific question. Was it It was not until I succeeded in getting natural three-dimensional procedure easy to get funded to pursue this? some actual results, working in my which was not as easy to implement spare time, that I applied for some NIH both technically and mathematically. PL For the first work I did it grant money. The reviewers of the [Two-dimensional imaging] was really myself on an existing [NMR] machine grant, according to what they told me a stop-gap solution. in the department, so just my time was later, said ‘this all sounds crazy’. On involved. Later the first funding was the other hand ‘all his other work has AE Did you ever identify later a through a mechanism that the NIH had been reasonable and normal, so maybe single moment when you knew it was at the time in which they would give a there is more to this than we think’. So going to work? certain small fraction of the institution’s they adjourned for the night and went NIH grants to the institution to spread back and looked at my proposal again PL No, more a moment - which around in whatever way it thought was the next day and decided that maybe didn’t feel like a really big moment - of useful for the early stages of research. there was something to it – they didn’t realising there was a principle that So I got probably overall $1000 or know quite what. So, essentially, my could be built on to do this. But after $2000 or something from that for very previous work led to serious that it was a matter of thinking through minor things - it was all very cheap at consideration of what might have been each of the things that would have to be the beginning. All the early tests and dismissed without further thought, so done if it were to be a practical the mathematical ideas were done on that was fortunate for me. technique, and that was spread over a paper with square grids in which I period of several weeks at least. carried out the mathematics by hand - A similar thing happened when I which again was just my time. There submitted the first manuscript to I don’t remember all the details, it was was no funding involved. I remember Nature. It was quickly returned and I just a matter of working away at the doing some of those calculations while wrote a long letter of protest to Nature various problems which presented sitting in dull seminars. I am sure the that they hadn’t understood it. They

Nuclear magnetic Tesla!) and also on the ‘local chemical sample a unique magnetic ‘signature’. resonance, MRI and the environment’ of the particular proton. Complex mathematical algorithms can Nobels then be used to reconstruct the image. The detailed magnetic properties of the Nuclear magnetic resonance (NMR) protons in water vary in different kinds As the Nobel web site explains was originally developed in the mid of living tissue because of subtle (http://www.nobel.se/medicine/laureates/2003/ 1940s, and won the American differences in the physical state of press.html): ‘Paul auterbur…discovered physicists Bloch and Purcell the Nobel water. A key early observation was the possibility of creating a two- Physics Prize in 1952. that the so-called ‘NMR relaxation dimensional picture by introducing times’ (an important magnetic gradients into the magnetic field.’ NMR relies on the magnetic properties property) of water protons differed Lauterbur published the first two- of certain atomic nuclei, including between tumours and normal tissues dimensional MR image in Nature protons. When placed in a strong (Damadian, 1971) (Lauterbur, 1973) magnetic field, the nuclei can orient themselves with or against the applied Magnetic resonance imaging (MRI) British co-winner Peter Mansfield field, giving states with different makes use of the inter-tissue variations ‘further developed the utilization of energies. Transitions between these in magnetic properties of water protons gradients… he showed how the signals states can be induced by irradiating the – which explains why different soft could be mathematically analysed… sample with radio-frequency energy. tissues look different in MR images. (and) also showed how extremely fast The excited state can then emit energy, Most critically, MRI depends on being imaging could be achievable.’ which as in other kinds of spectroscopy able to assign a signal to a specific has a characteristic frequency. This point in a three-dimensional sample Over 60 million investigations with frequency depends on the applied like a living tissue. The key is to put MRI are now performed a year magnetic field (typically 0.5-2 Tesla time-dependent magnetic field worldwide. for imaging and up to 60 Tesla for gradients across the sample, which spectroscopy – for comparison the gives any given point (or more References -4 Damadian R (1971). Science 171: 1151-1153. earth’s magnetic field is about 5x 10 correctly volume element) in the Lauterbur PC (1973). Nature 242: 190-191. 14 PN NOBEL PRIZE INTERVIEW apparently took another look, assigned PL I am surprised by two things and is so useful to the world, that I feel it to another reviewer and this reviewer and for two different reasons. One is that my whole life was not wasted’. said almost the same as the NIH had so-called functional MRI and looking at done - that I had done good things brain activation in various regions. AE I believe that there are now before, although this seemed crazy. He From very early on I thought there scanners you can stand up in. didn’t understand why it was of might be some physiological change in significance, but essentially thought it [active] regions of the brain which PL Whether that will be of any should be published,. might show up in magnetic resonance, practical use for anyone, no-one knows but the way in which it developed is yet. What has had an impact is the There was a similar reaction on the part quite surprising and the extent to which designs that provide a more open of people who were given the job by it is used now is very gratifying. The environment than the usual tube that my university of deciding whether or other was the extent to which heart gives many people claustrophobic not to patent ideas that were submitted imaging has become possible, because reactions. The designs work at lower as candidates for patents. They decided of the heart being a moving organ, - at field but provide more room to look that the chance it would ever make any least as long as the patient is in a around during the procedures; ‘a money was much less than the cost of condition where diagnosis is helpful! mother can hold her child’s hand’ like applying for a patent and therefore The idea that [MRI] techniques could the adverts say, and larger people can rejected it. But for that decision we be used effectively for a moving part of fit into them. The mainstream MRI might be holding this interview on my an organism was something we worked scanners were deliberately engineered yacht off the Riviera! The scepticism on very early on but it has evolved in a to be as economical and practical as in many quarters was very natural most gratifying way, further than I possible. Sort of like aircraft seats, considering what most people (in thought it could go. which to save money are made a little NMR) were doing and thinking. I bit small for most people. So [scanning don’t mean to imply that these people AE The growth in use of the anyone] over average size is difficult - were unusually lacking in appreciation technology in medicine is amazing. athletes, pregnant women, overweight of new work or were afraid of the Are you surprised by its extent? people, or just those who have the unusual. At one time a research fellow misfortune to grow up a bit larger than working in my own laboratory, actually PL About the practical most of us. What new designs for doing imaging, came into my office one applications. First of all it is hard to magnets in general will be accepted by morning, all dishevelled and upset, say whether I am surprised or not about the medical profession and be practical saying ‘it can’t work, it can’t work’. the worldwide extent. Obviously if it I don’t know. My reason for scepticism After calming him down, I tried to worked out at all it would get wide about the vertical walk-in design is that explain why his concerns were usage. On the technical side the almost for most purposes it is desirable to have irrelevant to its working. But he was a universal use of superconducting the patient very quiet – it is a lot easier trained physicist and could prove to me magnets for human whole body to be quiet lying down than standing that it wouldn’t work, even though he imaging has been a surprise. and fidgeting. The combination of fast was doing it! scanning by using Peter Mansfield’s techniques, and very high field magnets At the time I originally thought of these There were various other incidents like for greater sensitivity, could make ideas it was not even certain if any kind that, when people with a great deal of unconventional arrangements more of magnet could be made with the experience and good reputations in practical, but this is for the future to properties necessary for doing such an magnetic resonance claimed that it decide. could not work, or couldn’t be true. experiment. That superconducting [This was because of] reasons people devices could be scaled up to that size AE Many of the stories about had in their minds that seemed good was surprising for a couple of reasons, Peter Mansfield in England have enough reasons to them but were not one technical, the other financial. It emphasised that one of the things that actually relevant to the problems that I took a while for the potential usefulness is unusual about him is that he didn’t was working on. That of course is why of the developments and the go straight to university, but had a kind the problem was still there for me to improvement in the technology for of technical engineering apprenticeship work on about a quarter of a century making superconducting magnets to background. after NMR was [first] developed. It was come together and produce the useful the mental barriers that people had in devices that we now know. I remember PL I didn’t know this about Peter the way of seeing the possibilities of at one time visiting a manufacturer that Mansfield until I read the newspapers making images with the signals that had done research on, and built, recently. After my undergraduate had preserved the problem so that I superconducting devices and meeting degree I went to work directly in a would have a chance to work on it. there a very senior engineer who was research institute instead of going to practically in tears. He said: ‘I have graduate school because, for one thing, AE Of all the scientific and been working in this field all my life I had had enough of sitting in lectures medical applications of MRI there are and nothing has ever worked out - and listening to professors. I couldn’t now, which has surprised you the most? except this. This has worked so well, actually imagine ever being a professor, NOBEL PRIZE INTERVIEW PN 15 and then I was turned into one later. test scores in the entrance examination, provided some interesting moments But at the research institute where I people who were almost illiterate. We scientifically as well. worked you could also take classes at received only an abbreviated basic the same time at the University of training, then I was assigned, because AE You have won a lot of awards Pittsburgh graduate school and so I of my degree and experience, to the and been honoured before in various began working part-time on a graduate Army Chemical Centre, which was ways – I remember there used to be a degree at Pittsburgh and shortly after I devoted to chemical warfare and related picture on your office wall of you with started on that there was a diversion topics. President Reagan. Of course, the when I was drafted into the army for Nobel must be special ... about two years. Some [of us] had been drafted in the middle of graduate school, so we Joan Dawson No, that When I returned to graduate school I worked in the army laboratories where picture was on my wall! continued to work on my degree part- our nominal superiors were civil PL I was told for many years that time. The professor I was working servants who in general did not have the work was certainly a candidate for a with on a joint programme between modern training and experience Nobel but that could be said of many chemistry and physics – he was in because they had been hired some years things and many people. Stories get physics, I was in chemistry – decided before. Because the people they were around that you have been nominated, he was bored with the research he was drafting were very much up to date, though you are never supposed to hear, doing and left the University. So I was those people de facto ran the operation, but people gossip. I knew that I had left without a graduate advisor. Since although they had to get official been nominated, but that is very no-one else was interested in the work I permission for everything they did. was doing, my department head very different from actually being awarded the prize, so when Joan took the kindly offered to allow me to continue While I was there the army acquired an telephone call in October at 3.30 in the [and said] he would continue to take NMR spectrometer, [apparently] morning it was a surprise. Not a care of the necessary official because they happened to have unspent surprise that it ever happened, but a documentation, while I just supervised in the budget at the end of the fiscal surprise that it had happened this year. my own research, which he had no year just enough money to buy one. There is a lot of good work and a lot of confidence in himself. So I did most of Having leftover money in a good people out there, and the Nobel my research without a graduate Government budget is not something to Committee can only honour a few. supervisor. My work attracted notice be taken lightly, as generally you will and eventually I almost received a job have that much cut out of next year’s AE Has it changed your life? offer from a major university [until] budget. So there was an urgent need to someone there found out I didn’t have a spend it in a hurry, and they spent it all PL It has changed Joan’s life! [Ph.D.] degree, and the job offer never on an NMR machine. I found out from materialized. This brought home to me one of my friends in the barracks that Joan Dawson I have not had a that I should get my credentials. So I this was happening [and] because I had moment since that call early in finished up my thesis by stapling some connection with reading and October! Paul does not have a together a number of publications I seminars about NMR - but no practical secretary or admin assistant so I have already had and ended up with a experience - I was able to get myself been trying to take care of all the graduate degree. At the same time I assigned to that laboratory… arrangements, keep track of all the was being considered for a number of reporters, get back to them, and so on. other jobs, industrial and academic, and AE And the rest is history. someone from industry asked me why I PL Yes it has involved about would chose to take this academic job PL Well, I still had to get some 200% of Joan’s time. when I could have a much more practical experience! Parts of the machine were immediately returned to interesting and challenging job in AE Last question. Have you had to the manufacturers [to be upgraded]. industry. I told them simply that if I have a protocol lesson about meeting While I was waiting for the parts to be took the academic job it would be the King of Sweden? because in a [university] position I returned I did as complete a survey as I could do any silly thing I wanted to do could of the literature, which at that PL We have a Nobel Attendant rather than the job the company had for time consisted almost entirely of work and get a ‘walk through’ for all of it. me. And eventually I did, which by physicists on the magnetic moments They assign someone to each Laureate worked out very well. of nuclei and added up to perhaps 400 to make sure you don’t wander away or references on punch cards. This gave do something wrong. Who knows what AE Where did you serve in the US me more background than I had before. can happen to a stranger in Stockholm army, and what did you do? if they are not watched! When the parts came back I had a PL I was classified by the army in chance to do some practical one sense as a misfit. They had people experimental work on chemical warfare © Austin Elliott 2004 with graduate degrees, people with high agents which was a bit dangerous but 16 PN FEATURES

Can a single bout of exercise prevent decompression sickness? A single session of high-intensity exercise may form the basis for a novel approach to greatly reducing the risk of decompression sickness

formation (Dujic et al. 2004). Preliminary data from our laboratory also indicate that only strenuous exercise has a protective effect.

Mechanisms We currently think that nitric oxide Above, from the left: Ulrik Wisløff, Russell Richardson, Zeljko Dujic and Alf Brubakk (NO) influences bubble formation and thus is involved in the development of Decompression sickness (DCS) several weeks of daily aerobic training DCS. The body produces NO during following diving, during un-pressurized dramatically reduces the incidence of exercise; it is crucial for regulating aircraft flight or space flight severe DCS (e.g. Wisløff & Brubakk, breathing and blood flow, and there is extravehicular activity is believed to be 2001). These studies have postulated evidence that NO ’makes the inner initiated by the formation of gas rheological changes that alter the surface of blood vessels more slippery‘. bubbles in the tissue and blood. susceptibility to DCS, modified tissue Nitrogen bubbles are seeded like Nitrogen dissolves in the blood during perfusion, and reduced body fat (in crystals on rough surfaces: the dives, but comes out of solution if which nitrogen is more soluble). None smoother the blood vessels, the harder divers return to normal pressure too of these mechanisms are convincing, it is for bubbles to form. If the NO- rapidly - like bubbles coming out of particularly in light of the findings that production is blocked we observe a champagne when the bottle is a single bout of exercise is equally substantial increase in bubble uncorked. The predominant theory is effective as a longer training regimen formation; however, exercise still gives that bubbles grow from preformed and produces a short-term (1-2 days) protection despite NO-blockade, nuclei composed of small (approx. 1 reduction in decompression-induced suggesting that there is more than just micron) stable gas bubbles (Yount & bubble formation (Wisløff & Brubakk, Strauss, 1982). Nitrogen bubbles may 2001). cause effects ranging from skin rashes to seizures, coma and death. Even ‘Good’ and ‘bad’ exercise? though the risk of DCS is minimized by Initially we found that nitrogen bubbles changing the composition of the gas only formed in the blood of unfit rats. that is breathed and gradual However, by chance we noticed that decompression, DCS can still occur one bout of exercise 20 h prior to the unpredictably. Exercise has long been dive was just as beneficial as 6 weeks considered an additional risk factor for of exercise training. Fit rats sent on DCS, but recent studies in our dives 2 days after stopping exercise laboratory (Wisløff & Brubakk, 2001; developed as many bubbles as unfit Wisløff et al. 2003; Wisløff et al. 2004; rats. Thus, there was no beneficial Dujic et al. 2004) indicates that this effect of pre-dive exercise if the notion needs updating. exercise was performed too close (e.g. 0.5h, 5h and 10 h), or too far in During diving, gas must be breathed at advance (e.g. 48 h) of the dive time ambient pressure and tissue equilibrates (Wisløff et al. 2004). Furthermore, in with the elevated inspired inert gas agreement with Dervey et al. (2001), partial pressure forming a reservoir for unpublished results from our laboratory bubble growth; with exercise, tissues suggest that exercise immediately prior that receive increased blood flow to a dive promotes bubble formation. Figure 1 summarizes data for bubble formation and equilibrate more rapidly. By a separate Thus, there seems to be ‘good’ exercise incidence of death after a single bout of interval mechanism, exercise following diving and ‘bad’ exercise. Recently we running or chronic exercise (Ex), Nitric oxide donation or shortly before or after confirmed that a single bout of (NO) or inhibition (L-NAME), at different time points preceeding a simulated dive. Ex 48h pre-dive indicate decompression to altitude can promote strenuous exercise 24 h before a dive to that the single exercise bout was performed 48 hours bubble formation (e.g. Dervay et al. 18 m of seawater significantly reduced before starting the simulated dive. Ex 6wk, 48h pre- 2001). Exercise during the days the average number of bubbles in the dive indicates that the last exercise bout of chronic preceding diving has received little pulmonary artery in man, and that there endurance training for 6 weeks (5d per week) was performed 48 hours before the dive, etc. For details attention. There are three animal studies was no correlation between aerobic see references. Data are presented as median of all (mice, pigs and rats) and all reveal that capacity and amount of bubble our data for the respective groups. FEATURES PN 17

NO involved. Furthermore, both decay into gas micronuclei that can be necessary to provide a given degree of chronic and acute administration of an reactivated into bubbles, it is possible protection, and we must develop tools NO-donor protects against bubble that exercise without decompression to tell whether we are protected or not formation and death in rats (Wisløff et depletes the population of micronuclei. before diving. The understanding of the al. 2003; 2004) without performing Regeneration of the primordial mechanisms involved is, in our opinion, exercise. We speculate that both micronuclei population may take 10- critical as this may ultimately allow us exercise and NO hinder bubble 100 h (Yount, 1982), and this could to prevent DCS by biochemical means. formation via alterations in vascular explain the temporary protection endothelial properties since preexisting against bubble formation. Ulrik Wisløff1,2* gas nuclei are probably attached to the Russell S. Richardson1,3 endothelium, where they grow into Concluding remarks Zeljko Dujic4 bubbles that are dislodged into the Whether or not the effect of exercise on Alf O. Brubakk1 blood stream. However, if the bubble formation operates through the formation of NO as we hypothesize, or mechanism of exercise-induced 1Department of Circulation and Medical Imaging, suppression of bubble formation is through yet another mechanism, the Norwegian University of Science and Technology related solely to nitric oxide production, present studies significantly advance 2 Department of Cardiology, St. Olavs Hospital, then the timing of NO administration in our understanding of the effects of pre- Trondheim, Norway, Faculty of Medicine, Medical Technology Center, Trondheim, Norway relation to its prophylactic effects on dive exercise, and provide another 3 means of ameliorating the formation of Department of Medicine, University of California San bubble formation might be expected to Diego, La Jolla, CA, USA be similar. We recently reported bubbles upon decompression in 4 Department of Physiology and Biophysics, University (Wisløff et al. 2004) that administration humans. of Split School of Medicine, Split, Croatia of an NO-releasing agent reduced [email protected] bubble formation even when given 30 Since bubble formation is associated with decompression sickness, the References min prior to hyperbaric exposure Dervay JP, Powell MR, Butler B, & Fife CE (2002). The effect of (without any exercise). Thus, the timing studies (Wisløff & Brubakk 2001; exercise and rest duration on the generation of venous gas bubbles of the responses to exercise and NO Wisløff et al. 2003; 2004; Dujic et al. at altitude. Aviat Space Environ Med 73, 22-27. administration were quite different (as 2004) may impact broadly on the field Wisloff U & Brubakk AO (2001). Aerobic endurance training reduces exercise just prior to a dive was ‘bad of diving physiology. This work bubble formation and increases survival in rats exposed to hyperbaric pressure. Journal of Physiology, 537, 607 – 611. exercise’), indicating that it is probably potentially effects a large number of the not NO alone that results in the world’s population; in addition to pilots Dujic Z, Duplancic D, Marinovic-Terzic I, Bakovic D, Ivancev V, Valic Z, Eterovic D, Petri N, Wisloff U, Brubakk AO (2004). Aerobic exercise-induced protection. and diving professionals who are at risk exercise before diving reduce venous gas bubbles formation in of DCS as a consequence of human. J Physiol. 555: 637-642 An alternative explanation is that occupation, there are an estimated Wisloff U, Richardson RS, Brubakk AO (2004). Exercise and nitric exercise may have a direct effect on 854,000 new certifications for SCUBA oxide prevent bubble formation: A novel approach to the prevention of decompression sickness? J Physiol. 555: 825-829 micronuclei. Exercise before divers issued worldwide each year. decompression can enhance bubble Wisloff U, Richardson RS, Brubakk AO. (2003). NOS inhibition increases bubble formation and reduces survival in sedentary but not formation, but the effect is only At this point our data indicate that both exercised rats. J Physiol. 546:577-82. temporary, decaying with a half-life of timing of exercise and exercise intensity is critical. Before pre-dive Yount D & Strauss R (1982). On the evolution, generation and approximately 1 h in humans (Dervay regeneration of gas cavitation nuclei. J Acoust Soc AM 65, 1431- et al. 2002). It is likely that micronuclei exercise can be widely adopted as a 1439. predictable safeguard against DCS we are activated but the resulting micro- Yount D (1982). Journal of the Acoustical Society of America 71, bubbles dissolve if decompression does will need further standardization and 1473-1481 not occur during their lifetime. Since studies. For instance, we need a better only a fraction of dissolving bubbles understanding of how much exercise is News flash The original manuscripts discussed in this article and a Perspectives article relating to them, published in The Journal of Physiology (555, 637-642, 825-829 and 588), formed the basis of the first press release circulated by the Society’s new publisher Blackwell Publishing.

This resulted in articles in New Scientist (27 March, p 12) and two online journals - Medical News Today (http://www.medicalnewstoday.com) Figure 2. The figure depicts change in venous gas bubbles within the right heart and pulmonary artery following a dive without (A) and with (B) a previous bout of strenuous exercise in one diver. In A, there are numerous, and WebMDHealth clearly visible venous gas bubbles. After performing the exercise, bubbles are completely absent (B). (http://my.webmd.com) 18 PN FEATURES

Understanding skeletal muscle hypertrophy: integration of cell signalling All physiologists know that muscle activity is necessary to maintain muscle mass. But what are the underlying molecular mechanisms at work in the muscle? Here Douglas Bolster and colleagues offer some insights

Translation initiation and resistance exercise Translation initiation essentially encompasses two central components mediated by eukaryotic initiation factors (eIFs) that control rate-limiting events. These two components in simple terms allow the ribosome to bind to the mRNA (eIF4F complex) Left: front row (left to right): and to bring the ribosome to the site on Leonard Jefferson and Douglas Bolster; back row (left to right): the mRNA where translation begins David Williamson, Stephen (eIF2/eIF2B) (Fig. 1). An essential Crozier, Neil Kubica and Scot mechanism for regulating growth Kimball. Above: Peter Farrell within translation initiation involves the mammalian ‘target of rapamycin’ The vital importance of skeletal muscle susceptible to external modulation by (mTOR) protein. Two common to general health and daily activities is factors such as nutrient availability, downstream targets of mTOR are the likely taken for granted by most hormones, and exercise. 70-kDa ribosomal protein S6 kinase individuals. Skeletal muscle is (S6K1) and the eIF4E-binding protein- essential for basic posture, movement, Molecular regulation of 1 (4E-BP1). and a variety of metabolic functions. growth Specifically, skeletal muscle accounts The molecular controls that govern A common misconception regarding for approximately 40 - 50% of the total changes in protein synthesis and changes in translation initiation is that body mass, serves as the predominant eventual gain in muscle mass activation of any protein in this site for glucose metabolism and greatly incorporate both transcriptional and pathway corresponds with increases in contributes to the basal metabolic rate. translational inputs. Although protein synthesis. For instance, Maintaining or even enhancing skeletal exceptions occur, consequences following resistance exercise, muscle mass becomes critical in the associated with altered gene elevations in protein synthesis are context of aging (sarcopenia) and transcription generally occur over a delayed for several hours while mTOR- various disease states associated with period of days to weeks, whereas muscle loss (e.g. sepsis, cancer, effects attributed to mRNA translation diabetes, HIV). Thus, considerable (i.e. the process of synthesizing a efforts have been made recently to protein based on the information elucidate the cellular and molecular encoded by the mRNA) can be mechanisms by which skeletal muscle manifested within minutes to hours. loss (atrophy) and gain (hypertrophy) Transcription and translation each occur. Importantly, the processes that contain three distinct steps (initiation, invoke muscle atrophy are relatively elongation, termination) with the unique and do not appear to be the predominant regulation at the phase of simple reverse of hypertrophy. initiation. However, translation is unique because mRNA is recruited Increases in skeletal muscle mass are rather than produced and this process is dictated through the process of protein responsive to acute turnover, which is the balance between metabolic/nutritional alterations. The protein synthesis and protein focus of the present article will be to . breakdown. Higher rates of protein highlight the impact of mRNA Figure 1 Translational control of skeletal muscle protein synthesis following resistance exercise. synthesis relative to protein degradation translation initiation on acute changes Signalling through eIF2/eIF2B appears to control the must be maintained in order to achieve in protein synthesis, the upregulation of acute increases in global rates of protein synthesis hypertrophy, whereas elevated protein select mRNAs related to growth and after resistance exercise. How the mTOR pathway may regulate eIF2B is presently unknown. Activation breakdown will induce a loss of how these events culminate to alter of S6K1 and eIF4F proteins are mainly responsible for protein. Overall, these processes gene expression in the context of increasing the capacity to synthesize protein with continuously operate and are resistance exercise. chronic resistance exercise training. FEATURES PN 19

As we look to the future as to how our understanding of muscle hypertrophy will evolve it is important to acknowledge challenges as well. Comparison of data in this area of research is often difficult given the multitude of hypertrophy models currently employed. Tight correlation between cell culture and animal or human data does not always exist. Figure 2. Proposed model of cellular adaptations with resistance exercise. The immediate recovery period Furthermore, the overlap of various following resistance exercise involves translational regulation whereby distinct eIF proteins are activated and specific growth-related mRNAs are upregulated. Repeated bouts of resistance exercise incorporates signalling pathways and the rapidly transcriptional regulation and the specific mRNAs theoretically accumulate and new proteins are synthesized. expanding involvement of newly mRNA translation and transcription operate together to coordinate the eventual increase in skeletal muscle mass. identified proteins makes interpretation (E: exercise; Inactive mRNA: becomes active following each successive bout of exercise). complicated. The growth response by the cell incorporates multiple signalling mediated events can be rapidly these proteins may provide more inputs. An integrated response is upregulated during this period (Nader precise control for modulating a growth therefore required and, however & Esser, 2001). Eventual increases in response. Specifically, these responses tempting, hypertrophy will likely never protein synthesis appear to coincide appear temporal in nature and the acute be isolated to one key protein acting as with later eIF2B changes (Farrell et al. impact of resistance exercise on mRNA a ‘master switch’. Thus, a multi-faceted 1999). Without question, chronic translation likely becomes cumulative approach using genomic, proteomic and mTOR signalling is indispensable for with each successive bout of exercise; bioinformatic tools will be compulsory mediating increased cell size/muscle the implication being this growth to elucidate the gaps in our knowledge mass as inhibition of this pathway pathway is intermittently turned ‘on’ of how muscle hypertrophy occurs. almost completely blocks the response with repetitive resistance exercise and Douglas R Bolster1, Neil (Bodine et al. 2001). Additionally, the distinct mRNAs (ribosomal proteins, 1 1 downstream mTOR target, S6K1, is etc.) may accumulate to a point where Kubica , Stephen J Crozier , 1 strongly linked with muscle an increase in the amount of specific David L Williamson , Peter A 2 1 hypertrophy (Baar & Esser, 1999). proteins occurs (Neufer & Dohm, Farrell , Scot R Kimball and However, acute suppression of mTOR 1993). These responses highlight the Leonard S Jefferson1 does not appear to dramatically affect longer-term and more rapid control 1 overall rates of protein synthesis in mechanisms associated with The Pennsylvania State University College of skeletal muscle. Collectively, it is transcription and translation, Medicine, Department of Cellular and Molecular Physiology, Hershey, PA, USA accurate to propose that both respectively that contribute to achieving components of translation initiation are muscle hypertrophy (Fig. 2). 2East Carolina University, Department of Exercise and essential to increases in skeletal muscle Sport Science, Greenville, NC, USA mass. Events associated with eIF2B Where do we go from here? regulation may orchestrate the acute Identifying the key factors that rapidly References changes in protein synthesis following initiate the cascade of signalling events Baar K & Esser KA (1999). Phosphorylation of p70S6k correlates with resistance exercise, whereas activation in response to acute resistance exercise increased skeletal muscle mass following resistance exercise. Am J Physiol 276, C120-C127. of mTOR/4E-BP1/S6K1 may result in remain elusive but several candidates preferential synthesis of proteins may include integrin activation and/or Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, Bauerlein R, Zlotchenko E, Scrimgeour A, Lawrence JC, Glass DJ & necessary to enhance the translational calcium mobilization. Integrins are Yancopoulous GD (2001). Akt/mTOR pathway is a crucial regulator apparatus and optimize the capacity for transmembrane proteins that couple of skeletal muscle hypertrophy and can prevent muscle atrophy in . 3, 1014-1019. protein synthesis with long-term physical or chemical stimuli to vivo Nature Cell Biol training. intracellular events, whereas increased Bolster DR, Kubica N, Crozier SJ, Williamson DL, Farrell PA, Kimball SR & Jefferson LS (2003). Immediate response of mammalian target calcium flux is evident during muscle of rapamycin (mTOR)-mediated signalling following acute resistance Rapid cell signalling and contraction. The rapid, yet transient exercise in rat skeletal muscle. J Physiol 553.1, 213-220. resistance exercise upregulation of the pathway Farrell PA, Fedele MJ, Vary TC, Kimball SR, Lang CH & Jefferson Recent efforts to better understand demonstrated by resistance exercise LS (1999). Regulation of protein synthesis after acute resistance regulation of translation initiation suggests these factors could quickly exercise in diabetic rats. Am J Physiol 276, E721-E727. following an acute bout of resistance stimulate mTOR signalling which may Nader GA & Esser KA (2001). Intracellular signaling specificity in exercise suggest alterations wherein then lead to select mRNA translation of skeletal muscle in response to different modes of exercise. J Appl Physiol 90, 1936-1942. distinct eIF proteins are rapidly local growth factors (i.e. IGF-1), further phosphorylated (Bolster et al. 2003). upregulating the growth response by Neufer PD & Dohm GL (1993). Exercise induces a transient increase in transcription of the GLUT-4 gene in skeletal muscle. Am J Intermittent and transient activation of the cell. Physiol Cell Physiol 265, C1597-1603. 20 PN FEATURES

Bidirectional synaptic plasticity and motor learning in the cerebellum The learning of motor skills – fine movement control – depends upon the conversion of synaptic activity in the cerebellum into longer term changes in synaptic efficacy. Here Françis Crépel and Armelle Rancillac describe how stellate cells play a part

Synaptic plasticity and required for their induction, and by the motor learning underlying intracellular cascades (Lev- Ram et al. 2002). Classically, the cerebellum is considered as being devoted to postural Bidirectional synaptic adjustments and motor control. In plasticity in cerebellar keeping with this view, the geometrical interneurones Francis Crépel (left) and Armelle Rancillac organization of the neuronal network Other putative sites of synaptic within the cerebellar cortex (see Fig. 1) plasticity are present in the cerebellar and the apparent stereotyped properties cortex. In particular, stellate cells (SCs) of its main cellular elements made are inhibitory interneurones which neurobiologists believe until the 1960s receive the same excitatory afferents as that the cerebellum was a hard wired PCs (Fig. 1) and exert on these neurons ‘neuronal machine’ exquisitely adapted a powerful inhibition (Ito, 1984). In to motor control (Ito, 1984). However, principle, LTP or LTD at synapses because motor skills can be learnt, the between PFs and SCs should have a question arose as to whether the long-term counterpart on the inhibitory cerebellum is able to perform this task, action exerted by these interneurones despite its apparent rigid and almost on PCs, and thus contribute to long- crystalline structure. term changes in cerebellar output during motor learning. As can be seen in Fig. 1, Purkinje cells (PCs) are the only output neurons of In a recent series of in vitro Figure 1. Basic neuronal circuit in the cerebellum. the cerebellar cortex. In the late 60s, in experiments (Rancillac & Crepel, LTD = long-term depression. keeping with the then current views 2004), we showed that, depending on attributing learning and memory to the cells, either LTP or LTD can be enduring changes in synaptic efficacy induced at PF-SC synapses by in specific neuronal circuits, Marr and repetitive activation of PFs at low rate Albus proposed a theory which predicts (Fig. 2A). Moreover, pairing this low that when parallel fibres (PFs) and frequency stimulation with post- climbing fibres (CFs), i.e. the two synaptic depolarisation of SCs induced excitatory afferents to PCs, are a marked shift of synaptic plasticity in repetitively co-activated at low rate, favour of LTP (Fig. 2B). LTP at PF-SC synapses between PFs and PCs see synapses requires nitric oxide (NO) their efficacy durably depressed, a production as in the case of one of the phenomenon called long-term two forms of LTP at PF-PC synapses depression (LTD; Fig. 1). In this (Lev-Ram et al. 2002). In contrast, system, CFs are thought to carry error LTD at PF-SC requires activation of G- signals that instruct PF synapses which protein-coupled glutamate receptors. Figure 2. Synaptic plasticity at PF-SC synapses is were activated during incorrectly Finally, slightly higher frequencies of induced by stimulation or pairing protocols. A, plots of performed movements to decrease their PF stimulations induced a cAMP- the amplitudes, against time, of excitatory post- efficacy (Ito, 1984). Following early in dependent LTP at PF-SC synapses, like synaptic currents (EPSC) induced in SCs by PF vivo experiments by Masao Ito and the second form of LTP observed at PF- stimulations. At time=0 min, at protocol of stimulation of PFs at low rate (2 Hz for 1 min) was applied. colleagues, later in vitro experiments PC synapses in the same conditions Amplitudes are normalized to their respective control fully confirmed this model and (Lev-Ram et al. 2002). values. Each point is the mean ± sem of 5 separate unravelled intracellular cascades of experiments for LTP (upper plots) and 4 separate events leading to LTD (Daniel et al. Thus, PF-SC synapses exhibit LTP and experiments for LTD (lower plots). B, same as in A but LTD which are very similar to those when a co-activation (i.e. pairing) protocol (see text) 1998). Finally, two forms of the inverse was applied at time=0 min (n = 9). Note that LTD is no phenomenon, i.e. long-term potentiation existing at PF-PC synapses with, longer observed and that all plastic cells now express (LTP) of synaptic transmission between however, a major difference. At PF-PC LTP. C, reciprocal bidirectional plasticity of PF synaptic PFs and PCs, can be induced when PFs synapses, LTD is induced when PFs are input to PCs and SCs induced by a pairing or a activated at low rate in conjunction stimulation protocol. D, reciprocal bidirectional are stimulated in isolation at low rate plasticity of PF cutaneous receptive fields of PCs and (Fig. 2C). They differ from one another with stimulation of CFs which strongly of their afferent interneurones. by the frequency of stimulation depolarize PCs, whereas at PF-SC FEATURES PN 21 synapses, pairing low frequency At a more integrated level, PCs receive the cerebellum, such findings might stimulation of PFs with depolarization information from the periphery. In also help to understand how the of SCs strongly favours LTP. particular, in the forelimb projection cerebellum controls motor coordination Conversely, at PF-PC synapses, low area of the cerebellar cortex, PCs and per se. Indeed, an attractive hypothesis frequency stimulation of PFs alone interneurones receive information proposes that, following signal perfor- induces a NO-dependent form of LTP through PFs from well delineated and mance errors transmitted by CFs, the (Lev-Ram et al. 2002), whereas it rather small cutaneous areas, i.e. their corrective movement components could induces LTD in half of the plastic cells so called PF cutaneous receptive fields. be initiated or driven by events that at PF-SC synapses (Fig. 2C). In an elegant series of in vivo activate interneurone receptive fields experiments, Jörntell and Ekerot (2002) and braked or terminated by events that Relevance for motor learning demonstrated that, in this area of the activate PC receptive fields (Jörntell & During motor learning, when co- cortex, when PF are electrically Ekerot, 2002). activation of PFs and CFs leads to LTD stimulated alone or in conjunction with at PF-PC synapses, the same co- CF stimulations, unpaired PF Armelle Rancillac activation also occurs at the level of stimulations induce long-lasting Françis Crépel SCs, due to collaterals of CFs increases in the PF cutaneous receptive UMR CNRS, Paris, France impinging onto inhibitory interneurones field sizes of PCs and induce long- (Fig. 1). Such co-activation is therefore lasting decreases in PF cutaneous re- likely to induce LTP at PF-SC ceptive field sizes of their afferent References synapses, which in turn should interneurones, whereas the inverse is Jörntell H & Ekerot CF (2002). Reciprocal bidirectional plasticity of potentiate inhibition exerted onto PCs parallel fiber receptive fields in cerebellar Purkinje cells and their true for paired stimulations (Fig. 2D). afferent interneurons. , 797-806. by SCs, and thus reinforce the decrease Neuron 34 of responsiveness of PCs due to LTD. This reciprocal bidirectional plasticity Lev-Ram V, Wong ST, Storm DR & Tsien RY (2002). A new form of cerebellar long-term potentiation is postsynaptic and depends on Such a synergy between LTP at PF-SC of PF cutaneous receptive fields of PCs nitric oxide but not cAMP. Proc Natl Acad Sci USA 99, 8389-8393. synapses and LTD at PF-PC synapses and of their afferent interneurones fits Ito M (1984). The cerebellum and neural control. New-York, Raven might therefore play an important role very well with the bidirectional and Press, New-York. during motor learning. Similarly, LTD reciprocal synaptic plasticity at PF-PC Daniel H, Levenes C & Crepel F (1998). Cellular mechanisms of elicited at PF-SC synapses by repetitive and PF-SC synapses mentioned above cerebellar LTD. Trends Neurosci 21, 401-407. activation of PFs alone should also (Fig 2C and D). Besides their work in synergy with LTP induced in Rancillac A & Crepel F (2004). Synapses between parallel importance for understanding how fibres and stellate cells express long-term changes in synaptic PCs in the same conditions. information processing is managed in efficacy in rat cerebellum. J Physiol (Lond) 554, 707-720.

Something fishy here? we are sticking to the (?devalued) US literature, may I refer heavyweight Gramme-atical error? billion, i.e. one thousand million, by readers to my article ‘May the force be Nano-drolone? which their newspaper and most media with you’(Trends in Pharmacological Things were worrying enough for both has long since been seduced. The UK Sciences (1988), 9, 124-125). the Scottish salmon industry (toxicity billion is, of course, one million However, I must report that Brian scares) and tennis player Greg million. So a (UK) billionth of a gram Jewell rightly rubbished my shopping Rusedski (drug accusations) in January would actually be a picogram. skills for suggesting there that typical this year, but the Sunday Times made Cox’s and Bramley’s apples are of them a thousand times worse - quite Using these tiny (or immense) numbers similar mass. literally. Their article on Scottish and units requires either more care or salmon (11 January, p. 17) stated that should be avoided by the press. When I am currently pondering the use of the ‘the limit for dioxin in fish for human they claim to provide a definition they misleading term ‘microgravity’ that is consumption is 4 picograms per should please get it right. They make now a literature commonplace (>5k gramme. A picogram is a thousand our lives in the universities even more citations) to describe the situation in millionth of gram.’ No it isn't; that difficult. Here at Glasgow, we had to spacecraft orbiting the earth. In a straw defines a nanogram, of course. A explain to a first year student last term poll in my 400-strong physiology 2nd picogram is a million millionth of a where to find millimeters on his rule(r). year class this session, about half gram(me) - a thousand times smaller Since we all teach pharmacologists, believe(d) that humans would be than their 'definition'. All the more other bioscientists and medics too - the weightless on the moon. Should we amusing then that in the Sports section odd factor of a thousand too little or blame the press, or the schools? (See that day (p. 19), discussing Rusedski too much might just prove important – e.g. Gürel & Acer, Astronomical and nandrolone, Barry Flatman's piece even a matter of life or death! Education Review (2003), 2, 3). actually had a section headed ‘So how much is a nanogram?’ He reported it For criticism of a related, distressingly David Miller ‘is the equivalent of [sic] one billionth widespread practice of equating mass Institute of Biomedical & Life Sciences of a gram’. True, but only provided and weight, i.e. force, in the scientific University of Glasgow, Glasgow, UK 22 PN FEATURES

β The large conductance calcium-activated potassium channel (BKCa) and the 2 adrenergic receptor (AR): a direct link to uterine relaxation β The similar pattern of expression between the 2 adrenoceptor and BKCa channel during pregnancy suggests that the link between these two proteins may constitute a new piece in the jigsaw

Preterm birth and its attendant sequelae during most of gestation to one of impose a major burden on health and powerful rhythmic contractility at educational resources, in addition to the parturition determined by an emotional and personal costs to upregulation of contraction-associated families and individuals affected by proteins (CAPs) such as gap junctions Fiona Broughton Pipkin (left), Boonsri Chanrachakul prematurity. The NHS reportedly and oxytocin receptors. and Raheela Khan spends nearly £40K on each baby β β weighing < 1000 g (Petrou, 2003). The 2 adrenergic receptor ( 2 AR), a Over £70 million is spent by the NHS member of the superfamily of G each year for neonatal intensive care, protein-coupled receptors, is abundant even excluding associated health care in smooth muscle organs. Activation of β costs for neurological or respiratory the 2 AR results in uterine smooth problems. Indirect costs are muscle relaxation. Currently, drugs β β incalculable arising as a result of, for which act at the 2 AR, 2 agonists example, loss of employment to care (ritodrine, terbutaline) are widely used for a preterm baby. as a main treatment option for preterm

During the past three decades, the advent of sophisticated medical technologies in neonatal paediatrics has greatly improved the survival rate of premature babies. Indeed, this has pushed prematurity to the extremes of viability and presents its own paradox: survival but at what cost? Babies born at extreme preterm gestations have a Figure 1. H & E staining of formalin-fixed human good chance of survival but with myometrium demonstrates, A (top) densely packed questionable quality of life. To date, myometrial cells with small spindle-like nuclei in there is no sign of a breakthrough in the nonpregnant women whereas, in B, cells have a prevention or treatment of preterm bigger nucleus with more cytoplasm in pregnant women. labour. This may be attributed to our limited knowledge of the complex mechanisms that determine uterine Preterm birth, which is the delivery of excitability, the quiescence during an infant before 37 completed weeks of pregnancy and its physiological gestation, is a leading cause of perinatal removal at term. mortality and morbidity. It accounts for 6-11% of births and the number is The change in size and contractile twice as much in developing countries. behaviour of the human uterus with It is noteworthy that the incidence of pregnancy is dramatic. Myometrial preterm delivery has risen in the USA cells of the gravid uterus are 5-10 times from 9.4% in 1981 to almost 12 % in larger compared with their non- 2000. This is despite considerable pregnant equivalents, due to cellular research efforts into the prevention and hypertrophy during pregnancy. This is management of preterm labour. observed as an increase in size of the Predictive methods such as ambulatory nuclei and the amount of cytoplasm in monitoring and assessment of risk individual cells (Fig. 1A and 1B). factors have not proved to be reliable Moreover, the uterus is transformed Figure 2. Immunofluorescence of myometrial cells from term pregnant women show that positive staining for (A) 2 AR and (B) indicators in identifying patients at risk. from a state of relative quiescence BKCa channel is predominantly localized at the plasma membrane. FEATURES PN 23 labour. However, they are associated with adverse maternal cardiovascular and metabolic effects due to the ubiquitous distribution of this receptor in many other target organs. Further, β the efficacy of 2 AR agonists is compounded by the development of tachyphylaxis after continued exposure to these agents both in vivo and in vitro. Considering this, there is a paucity of information regarding the molecular β basis of 2 AR function in uterine smooth muscles of pregnant women before and after the onset of labour.

We recently reported the plasmalemmal β Figure 3. A schematic representation of pathways leading to control of uterine activity. Elevation of intracellular calcium from calcium influx and location of 2 ARs in pregnant human release from sarcoplasmic reticulum (SR) activates BKCa channels resulting in uterine relaxation. BKCa channels are likely to have an myometrial cells (Fig. 2A), levels of important functional role in 2 AR mediated-relaxation in the human myometrium which are down-regulated in pregnant β women with labour compared with (Chanrachakul et al. 2003a; Matharoo- strategies that target the 2 AR/BKCa those not in labour (Chanrachakul et al. Ball et al. 2003). pathway for the treatment of preterm 2003b). However, it remains unclear labour to reduce the incidence of whether this transition precedes the Uterine contractions result from an prematurity. 2+ onset of labour or whether it occurs as elevation of intracellular Ca which in a consequence of it. turn activate BKCa channels leading to Acknowledgement uterine relaxation, but cellular control Boonsri Chanrachakul is supported by An increasing body of evidence of this pathway is not fully understood. the Faculty of Medicine, Ramathibodi β supports the notion that ion channels A prominent feature of 2 AR Hospital, Mahidol University, Thailand. may be the terminal effectors in stimulation is their linkage to the Boonsri Chanrachakul signalling cascades and as such are activation of BKCa channels (Kume et β Fiona Broughton Pipkin probably linked to a diversity of al. 1989). In the human uterus, 2- Raheela N Khan specific signalling pathways. agonists activate BKCa channels causing cellular hyperpolarization via G Academic Division of Obstetrics and Gynaecology, Calcium-activated potassium channels protein-dependent pathways. However, School of Human Development, University of are richly expressed in smooth muscle the molecular basis of the interaction Nottingham, Nottingham, UK organs including the human between these two proteins in myometrium. Of the three subclasses mediating uterine relaxation and the References of calcium-activated potassium onset of labour in humans is not Chanrachakul B, Matharoo-Ball B, Turner A, Robinson G, Broughton- channels, the large conductance Pipkin F, Arulkumaran S & Khan RN(2003a). Immunolocalization and known. Interestingly, our recent data protein expression of the alpha subunit of the large-conductance calcium-activated potassium (BKCa) suggests that there is an apparent calcium-activated potassium channel in human myometrium. channel predominates in human colocalization and a direct protein- Reproduction 126, 43-48. β myometrium and is involved in protein interaction between the 2 AR Chanrachakul B, Matharoo-Ball B, Turner A, Robinson G, Broughton- mediating uterine relaxation (Khan et Pipkin F, Arulkumaran S & Khan RN (2003b). Reduced expression of and BKCa channels in the term, pregnant immunoreactive beta(2)-adrenergic receptor protein in human al. 1993). The BKCa channel comprises human myometrium (Chanrachakul et myometrium with labor. J Clin Endocrinol Metab 88, 4997-5001. α a pore-forming subunit and a al. 2003c). β Chanrachakul B, Turner A, Matharoo-Ball B, Broughton Pipkin F, regulatory subunit. Arulkumaran S, Khan R N. (2003c). Colocalization and expression of β We consider it to be of significant 2-adrenergic receptor and large conductance calcium-activated potassium channel in human myometrium. C8. Previous data regarding the expression importance to examine the correlation Proc Phys Soc 551P, β of BKCa channel mRNA and protein in between 2 AR and BKCa channel in Khan RN, Smith SK, Morrison JJ & Ashford ML (1993). Properties of large conductance potassium channels in human myometrium during mouse and rat myometrium showed much greater detail. Our ongoing pregnancy and labour. Proc R Soc Lond B Biol Sci 251, 9-15. conflicting results. We demonstrate studies are focussing on the molecular β Kume H, Takagi K, Tokuno H & Tomita T (1989). Regulation of Ca- that, as for 2 AR, BKCa channels are and functional association between dependent K-channel activity in tracheal myocytes by predominantly localized to the these two entities in human phosphorylation. Nature 341, 152-154. myometrial cell membrane (Fig. 2B) myometrium and their contributions to Matharoo-Ball B, Ashford ML, Arulkumaran S & Khan RN (2003). and that levels of both the α and β myometrial relaxation signalling Down-regulation of the alpha- and beta-subunits of the calcium- activated potassium channel in human myometrium with parturition. subunit of the BKCa channel decline in cascades. Biol Reprod 68, 2135-2141. parallel in myometrial tissues obtained Hopefully, these findings will lead to Petrou S (2003). Economic consequences of preterm birth and low following the onset of labour of both birthweight. Bjog 110, Suppl 20, 17-23. term and preterm pregnancy the development of novel therapeutic 24 PN FEATURES

Imaging the activity of single calcium channels: ‘optical patch-clamp recording’ ‘Total internal reflection’ sounds a bit navel-gazing, but is actually a microscope technique that can allow ion flow through single channels to be observed optically. Here Angelo Demuro and Ian Parker explain how

level is feasible. In part this is because of the availability of highly sensitive and selective fluorescent Ca2+ indicators. More importantly, it also reflects the enormous changes in Ca2+ concentration that occur near the mouth of an open Ca2+ channel. Since the resting cytosolic [Ca2+] is maintained at a few tens of nM the local concentration can increase 1,000-fold when a Ca2+-permeable channel opens, whereas corresponding changes for ions such as Na+ or Cl- are less than 10-fold.

The first unequivocal experiments imaging Ca2+ flux through single Angelo Demuro (left) and Ian Parker at the finish line of the Badwater Ultramarathon through Death Valley channels were made by Zou et al. (1999), who used widefield Ion channels regulate the activity of invasively image the activity of fluorescence microscopy in conjunction virtually all cells - both electrically numerous individual ion channels with whole-cell electrophysiology to excitable and inexcitable. Our ability within a cell, or even within cells in an show fluorescence signals to study these channels was intact tissue or organ. One potential accompanying openings of individual revolutionized following the invention method involves the use of fluorescent caffeine-activated channels in the of the patch-clamp technique by Erwin reporters of protein structure membrane of smooth muscle cells. The Neher and Bert Sakmann (Neher & (Sonnleitner et al. 2002) – for temporal and spatial resolution in their Sakmann, 1976), which allows currents example, targeted exogenous dyes, or records, however, was poor: to be recorded through single channels GFP-tagged ion channels – to obtain a fluorescence signals rose and fell over a with exquisite (sub-pA and sub-ms) readout of conformational changes in few hundred ms during and after resolution. Nevertheless, patch- channel structure associated with its channel openings, and spread over tens clamping has some limitations. Among opening. This has the advantage of of micrometres. This degradation them, little or no information is providing biophysical information arises simply from the diffusion of obtained regarding the subcellular about channel functioning, but faces Ca2+ ions (and of Ca2+-bound indicator distribution of channels; it is not daunting problems of weak signals and molecules) away from the ‘point possible to record independently from rapid photobleaching because only one, source’ of the channel. more than one channel at a time; and or a few, fluorophore molecules are trauma associated with giga-seal conjugated to each channel. Improvements in spatial and kinetic formation may disrupt the local resolution should thus be achieved by cytoskeleton and thereby affect channel An easier approach involves the use of restricting fluorescence measurements function. There is also the practical fluorescent probes that sense the ions to the close vicinity of the channel matter that patch-clamping requires a passing through a channel. This mouth, where changes in [Ca2+] are lot of patience – each pipette can be provides a built-in amplification, as largest and rapidly track the opening used only once, and in every patch- thousands of ions per ms typically flow and closing of the channel. Indeed, clamp lab there is an old coffee tin (or through an open channel – indeed, that better results were subsequently nowadays, an officially-approved is what makes patch-clamp recording obtained using confocal microscopy to sharps bin) containing hundreds or possible. Moreover, optical recording monitor fluorescence from sub thousands of discarded pipettes. offers further gain, because a single femtolitre cytosolic volumes (Wang et fluorophore molecule can emit al. 2001; Demuro & Parker, 2003). Optical single-channel thousands of photons per millisecond. However, there are practical limitations imaging There is a limitation, however, as to as to how fast the confocal laser spot For these reasons, there has been much which ions can be sensed, and Ca2+ ions can be scanned, necessitating a trade- interest in developing optical are at present the only species for off between spatial and temporal techniques that could allow us to non- which detection at a single channel resolution. Those studies thus used FEATURES PN 25 linescan imaging, in which fluorescence is monitored along only a single line in the cell, typically scanned every 2-8 ms. This has significant disadvantages in that spatial information is restricted to a single dimension, the scan line intersects only a few channels, and distorted signals arise from out-of-focus channels to either side of the scan.

Total internal reflection fluorescence microscopy To circumvent these limitations we have explored the use of total internal reflection fluorescence microscopy (TIRFM) for rapid two-dimensional Figure 1. A, principle of TIRFM imaging. Excitation light (blue) from a laser is directed at a shallow angle through 2+ a coverglass, so that it undergoes total internal reflection at the interface with an aqueous solution (Ringer’s imaging of cytosolic Ca signals solution). This creates an evanescent field extending ~ 100 nm from the interface, which can excite fluorescence arising very close to the cell membrane (green) in a dye-loaded cell in close proximity to the coverglass, allowing imaging of the microdomain of Ca2+ (Axelrod, 2003). TIRFM works by (red) around the mouth of an open Ca2+-permeable channel. B, pseudocolored representation showing 3 directing excitation light through a sparklets (single-channel openings) in a 60 µm square region of oocyte membrane. C, schematic of the system 2+ glass substrate toward an aqueous used for TIRFM imaging and voltage-clamp activation of Ca channels expressed in Xenopus oocytes. (adapted from Demuro & Parker, 2004). specimen at a sufficiently shallow angle that total internal reflection occurs due to the refractive index decrease at the glass/water interface. However, a very thin electromagnetic field (evanescent wave) with the same wavelength as the incident light is created in the liquid, and decays exponentially with distance from the interface (typically over one or a few hundred nm). Because this field is able to excite fluorophores near the interface while avoiding excitation further into the aqueous phase, it provides an ‘optical sectioning’ effect similar to, but even narrower than, that achieved by a confocal microscope.

Although the idea of TIRFM is old, its biological utility has expanded greatly in the last few years with the development of specialized oil- Figure 2. Imaging the activity and localization of single N-type channels expressed in the oocyte membrane. immersion objective lenses with very A, single video-frames showing TIRFM fluorescence at rest, and after depolarizing to activate channels. Each spot 2+ high numerical aperture (1.45 or (sparklet) in the lower panel arises from Ca flux through an individual channel. B, measurements of channel gating obtained by recording local fluorescence signals at sparklet sites. Examples are shown of simultaneous greater). These allow the excitation recordings from 10 channels. Note the variation in gating properties. Some channels (red) showed only a single, light to be directed to the specimen at brief opening immediately on depolarization, whereas others (blue) showed continued, longer openings throughout the necessarily shallow angle through the depolarizing pulse. C, N-type channels are immobile in the oocyte membrane. Panels show high- the very edge of the lens while using a magnification views of sparklets at a given site during repeated depolarizing pulses over a period of about 5 min. Green crosshairs are centered on the first event. D, map shows the locations of sparklets within a region of high-sensitivity c.c.d. camera to membrane. visualize fluorescence in the evanescent field through the same objective with the Ca2+ indicator fluo-4 dextran pulses (applied via a two-electrode (Fig. 1). (Demuro & Parker, 2004). After voltage clamp) then evoke numerous, stripping away their surrounding transient flashes of fluorescence 2+ Imaging Ca channels vitelline envelope, oocytes adhere (‘sparklets’, Fig. 2A). Several lines of expressed in oocytes closely to a coverslip, so that the cell evidence indicate that the sparklets We tested the ability of TIRFM to membrane and immediately adjacent reflect openings of single N-type 2+ resolve Ca flux through individual N- cytoplasm lie within the evanescent channels: they are absent in control type voltage-gated Ca2+ channels field, with only a thin intervening film oocytes; their fluorescence magnitudes expressed in Xenopus oocytes injected of extracellular solution. Depolarizing correspond to expected single-channel 26 PN FEATURES FEATURES PN 27

Brain waves plainly speaking Recent studies of brain waves (oscillations) generated by the hippocampus reveal how a large collection of nerve cells turns into a living brain tissue. These oscillations are brain- specific integrative network activity, adopted through the collective properties of the network, and not supported by the activity of individual cells

What is the most characteristic function cells underlies the oscillatory activity. of the brain known? The answer is Action potentials are an all-or-none straightforward – brain waves, known type of signal that represent a form of a in scientific terms as oscillations. ‘decision’ at the single cell level that Indeed oscillations, a brain specific provides the cell with the means to phenomenon, are a hallmark of the communicate this ‘decision’ to other living brain. Since their discovery, in cells. Yacov Fischer the late 1920s, oscillations (and the resulting EEG) have been suggested to This concept, first discovered in be involved in a variety of normal invertebrate neurons, demonstrates that activities and pathologies of the brain, the basic principles of neuronal and to be critical to many ‘higher’ brain function are consistent throughout the functions. It is therefore conceivable species. However, in invertebrates, that oscillations are likely to represent a where the nervous system consists of a basic operational principle of the brain small number of neurons, the function and its organs. of every neuron is critical; in the mammalian brain, where neurons are Indeed, Grey Walter showed in a series abundant, it is not necessary for every of studies that were ahead of their time neuron to exhibit action potential firing (1950s) that robots built to implement to support their function. the biological principles of oscillations could exhibit self-awareness, ‘New’ concepts consciousness, learning, recognition of Direct measurements of the activity of other members of the group, and social individual cells of the hippocampal Figure 1. Axonal pathways intrinsic to the behaviours. network show that oscillations depend hippocampus. Three main intrinsic axonal pathways exist in the hippocampus: the Mossy fiber-, the on sustained synaptic activity. It is Schaffer collateral-, and the Associative pathway. In To address the ‘old’ and ‘new’ therefore reasonable to assume that a contrast to the other pathways, the associative conceptions regarding oscillations, I mechanism based on sustained synaptic pathway does not convey information between the shall concentrate only on oscillatory activity underlies the EEG signal, rather hippocampal subfields (DG, CA3, CA2, and CA1). Instead, recent data show that the associative activities that are related to the than an action potential based one. pathway is critical for the adaptation of an oscillatory hippocampus. The hippocampus is mode of activity by the hippocampus. particularly suitable for the study of There is increasing evidence that an oscillatory activity, since it is the source action potential-based mechanism does How the brain works remains largely an for theta oscillations (~8 Hz), a not support the sustained synaptic inaccessible question which we, as prominent brain wave, and contributes activity. This is because the numbers of researchers, lack the conceptions and to the brain’s gamma activity (~40 Hz). action potentials provided by the tools to address. principal cells are too low, and the These rhythmicities are a brain-specific properties of discharge in the inhibitory However, we can deal with a integrative network activity that is cells are not always consistent with manageable problem by rephrasing the suggested to be critical to the function initiation, frequency-control, question to: what characterizes the of this organ and of the brain. synchronization and pacing of the activity of the living brain, and how Therefore, understanding the oscillations. This is further illustrated does it translate to the functions we underlying mechanisms would reveal when considering the energy assign to the brain? By solving this the principles governing the integrative constraints on the tissue, where action basic question, we are able to learn network function (oscillations) of the potentials consume a large part of the important information about the organized neuronal ensemble (the brain’s energy, and cannot be sustained principles that govern the function of a hippocampus). at high rates for long. large group of neurons as a living brain tissue, and in turn reach the position ‘Old’ concept Gap junctions are likely to be a critical where we can think of ways to address It is believed that the firing pattern of element in the integrative function of more complex questions. action potentials of the hippocampal the hippocampus to adapt an oscillatory 28 PN FEATURES mode of activity. This notion was does not seem to convey information significant breakthroughs in our brilliantly introduced in the theoretical between different regions of the understanding of the brain and its work of Roger Traub who, without any hippocampus. The mechanism function. They also demonstrate that data, connected the physical entity of underlying sustained synaptic activity is studying the principles of integrative the gap junction and the theoretical accounted for through functional function in organized neuronal notions of interactions in large activation of this pathway, action ensembles is a realistic approach to networks to be the element to sustain potential discharge of contributing significantly advance our knowledge, the interaction in the large network that cells, and gap junction mediated and that neurophysiology and would influence its own function. This interactions. Such a mechanism, based electrophysiology are still among the notion is now further supported by on the principles of distributed most powerful tools, when physiological, anatomical, and processing in a large axonal network, appropriately used, for studying the pharmacological correlative data. formation of a reverberatory system, function of the brain. and existence of a random and The hippocampal associative pathway, distributed probabilistic ‘clock’, Yacov Fischer one of the large axonal pathways explains how oscillations are initiated, Brain Research Institute, University of Zurich, intrinsic to the hippocampus, is the core maintained, synchronized, and paced, Switzerland ([email protected]) element underlying the adaptation of and how specific patterns are adapted. the oscillatory mode of activity by the The solution offered by such a References hippocampal network. This pathway, mechanism is robust and supports the Attwell D & Laughlin SB (2001). An energy budget for signalling in originally discovered by Lorente de Nó idea that the oscillations are important the grey matter of the brain. J Cereb Blood Flow & Metab 21, 1133- 1145. in the 1930s, is now found to be one of for the natural function of the the central solutions that allows the Fischer Y & Dürr R (2003). Inhibitory control of intrinsic hippocampal hippocampus. oscillations? Brain Res 982, 79-91. hippocampus to support an oscillatory Fischer Y (2004). The hippocampal intrinsic network oscillator. J mode of activity under physiological With these new concepts, we can see Physiol 554, 156-174. conditions. The pathway consists of a some of the solutions that exist at the Traub RD & Bibbig A (2000). A model of high-frequency ripples in the large collection of axonal collaterals network level to support the integrative hippocampus based on synaptic coupling plus axon-axon gap that unlike other intrinsic pathways function of the brain tissue. These are junctions between pyramidal neurons. J Neurosci 20, 2086-2093.

Getting insight into the work of tendons Oksana Kostyuk and Robert Brown describe how a novel fibre-optic spectroscopic technique based on light-scattering can provide structural information on tendon changes tissue is collected by a second fibre for this tight-packed organised structure analysis. This ‘backscattered’ light means that the tendon is weaker, less contains a wealth of information about efficient in transmitting forces and the composition and structure of the prone to break suddenly. Detecting tissue. A major challenge, however, is such changes early, predicting an to understand just what this impending rupture, or following the overwhelming amount of spectral data repair after injury would be equally Oksana Kostyuk (left) and Robert Brown means and to ‘dig up’ something useful valuable for humans and, for instance, for diagnostics, for instance to spot racehorses. At the moment there is no early stage skin cancer (Wallace et al. way to measure structural changes in It is amazing how our quest for 2000). Another example would be to living tendons non-destructively and knowledge goes in circles. People have detect early degeneration of the certainly not without a hospital and a always used light reflected by skin for Achilles’ tendon, for example, after million pound MRI scanner. Both MRI diagnostics. Remember those typical injuries in footballers. and ultrasound can provide images questions: ‘you look a bit pale today, showing the size and swelling of the are you all right?’ Or: ‘what is that Tendons are the connective tissues tendon, but such qualitative information rash, have you got an allergy?’ Now which transmit mechanical forces from needs skilled interpretation and remains science is trying to make use of this muscles to bones. To fulfil this largely subjective. In addition, the ancient knowledge in a more function, a rope-like, tough, fibrous changes detected with these techniques systematic and quantitative way. In our structure has evolved, formed by the are probably characteristic of rather centre we use elastic scattering well-aligned fibrils of collagen, the later stages of the tendon degeneration. spectroscopy (ESS). Its basic principle most abundant body protein. Such a is not as dramatic as it sounds: non- well-organised structural arrangement In our recent paper (Kostyuk et al. harmful white light is flashed onto the is characteristic of a healthy tendon, but 2004) we reported how an ESS-based surface of the tissue via an optical fibre it becomes less organised as the tendon technique was used to non- and the light that comes back from the degenerates, ages or is injured. Loss of destructively study structural changes FEATURES PN 29 during in vitro loading of the horse superficial digital flexor tendon, analogues to the human Achilles’ tendon. We used the phenomenon of the backscatter anisotropy (unequal distribution) found in tissues formed by aligned fibres like muscle (Marquez et al. 1998) or with partial alignment of structural fibres such as skin (Nickel et al. 2000). When light was delivered to the surface of a normal tendon sample, Distribution of light in a matching pair of horse superficial digital flexor tendons: normal (Figure 1, left) and an elongated, elliptical ‘aura’ of light degenerated (Figure 2, right) distribution in the tissue was apparent (Fig. 1). Much more backscatter was impression: it had a value of about 8 endo/arthroscope or even via a surgical detected when the probe was positioned for the normal control tendon (similar needle. Together with a relatively cheap parallel to, rather than perpendicular to, to the previous study), but in case of basic spectroscopic set-up and a simple the tendon fibres (the probe was held the degenerated tendon it was equal to data analysis algorithm, this technique perpendicular to the tendon surface and only about 1.2 in the area of the visible may represent a major research and rotated to achieve different detection lesion and about 2.5 when measured 10 diagnostic advance. angles). To characterise this backscatter cm away from the lesion. We are now anisotropy we calculated an Anisotropy carrying out ultrastructural Acknowledgements Factor (AFλ), as a ratio of maximum to investigation of these tendons to The authors are grateful to Helen Birch minimum intensities of backscatter (at complement the ESS findings. for providing the horse tendon samples λ any given wavelength, ). Where the and to Mary Morgan for her help with amount of light travelling in different Thus, this non-destructive real-time the imaging of the tendons. directions is the same (circle-like fibre-optical technique can provide ‘aura’), this ratio is one, but it increases structural information on changes in Oksana Kostyuk rapidly as the backscattered ‘aura’ tendons under load or due to pathology. Robert Brown becomes elliptical. In relaxed tendons It can be used to study in situ Tissue Repair & Engineering Centre the AF500 was around 7, but it increased physiological structural changes in Institute of Orthopaedics up to 18.5-fold when tendons were tendons and ligaments during use Royal Free and University College Medical School stretched in a material testing machine. (Morgan et al. in preparation). It has London, UK also proved to be an effective means for Encouraged, we applied ESS to study monitoring development of the collagen References tendon pathology, investigating fibril alignment as tissue-engineered Kostyuk O & Brown RA (in press). Novel spectroscopic technique for in situ monitoring of collagen fibril alignment in gels. Biophys J. matched pairs of horse tendons, one constructs matured in culture (Kostyuk normal and the other clearly & Brown, in press). It seems beyond Kostyuk O, Birch HL, Mudera V & Brown RA (2004). Structural changes in loaded tendons can be monitored by a novel degenerated with a pronounced lesion. doubt that ESS-based techniques have spectroscopic technique. J Physiol 554, 791-801. This pathological change in the tendon huge clinical potential as diagnostic and Marquez G, Wang LV, Lin SP, Schwartz JA & Thomsen SL (1998). structure produced near circular ‘aura’ monitoring tools in medicine and tissue Anisotropy in the absorption ans scattering spectra of chicken breast of backscatter (Fig. 2). More engineering, particularly as ESS seems tissue. Appl Optics-OT 37(4), 798-804. interestingly, however, even far away to be able to ‘see’ early structural Nickel S, Hermann M, Essenpreis M, Farrell TJ, Krämer U & from the lesion region of the tendon, changes in the tissues. Recent advances Patterson MS (2000). Anisotropy of light propagation in human skin. the backscatter ‘aura’ was still rounder in fibre-optic technology make it Wallace VP, Crawford DC, Mortimer PS, Ott RJ & Bamber JC (2000). than the elliptical one of a normal possible to design really thin optical Spectrophotometric assessment of pigmented skin lesions: methods tendon. The AF confirmed this and feature selection for evaluation of diagnostic performance. Phys 500 probes that could be applied via an Med Biol 45(3), 735-751.

Wonderful collaboration, with additional support from Exhibition dates are: Wonderful: Visions of the Near Future is a Arts Council England, and has been different kind of art show – one that inspired by today’s artistic and scientific 18 September-1 October, 2004 – Magna, questions what it means to be ‘wonderful’ developments, suggesting possible futures Rotherham in this time of rapid technological advance as they may be in 5, 10 or 100 years. and cultural instability. This major new 28 November, 2004-9 January, 2005 – project emerges from the timely discussions These are not the utopian or distopian Cornerhouse, Manchester and realizations of artists and scientists visions of science fiction, but the working together collaboratively to discoveries of artists and scientists working Contact: Maria Fusco, Press Consultant for investigate and create shared experiences collaboratively to test our responses to Wonderful and discoveries. The project is a Wellcome ethical questions and to develop industrial Tel: 07720 775 093 Trust and National Endowment for Science, prototypes based on concepts taken from Email: [email protected] Technology and Arts (NESTA) art. Website: http://www.wonderfulwebsite.net 30 PN FEATURES

Vasopressin may limit its own secretion with the help of pituicytes Vasopressin released from the pituitary is a critical controller of body water balance. Like many hormones, it seems to be able to inhibit its own release. Jean-Marc Mienville and colleagues discuss the possible underlying mechanisms

a high output of neurohypophysial Relevant to our findings, two particular hormones. Numerous converging data features of this secretion are (1) the fact led Hatton (1988) to propose a model that it also occurs within the interstitial whereby activated pituicytes retract space of the neurohypophysis, and (2) both from between secretory terminals, that ATP is present in the vesicles (see thereby increasing their excitability, and Rosso et al. 2004 for details). As a away from the basal lamina of the consequence, pituicytes are likely to be perivascular space, whose increased exposed to both vasopressin and ATP Lia Rosso (left), Jean-Marc Mienville (centre) and contact with terminals ought to every time secretion is activated. Brigitta Peteri-Brunbäck facilitate hormone release into the To maintain homeostasis, organisms blood. Both vasopressin and oxytocin Because ATP is quickly broken down to often resort to various mechanisms of are synthesized in the magnocellular adenosine by specific enzymes present negative feedback. This is particularly nuclei of the hypothalamus; they are in the neurohypophysis, we investigated true of secretory processes, a classical axonally transported to the whether the latter compound could be example being the output of neurohypophysis where they are one of the signals involved in the catecholamines, which is self-regulated released into the blood. Vasopressin (or morphological changes observed in through inhibition of tyrosine anti-diuretic hormone) plays a crucial pituicytes. Using in vitro cultures, we hydroxylase (the enzyme that catalyzes role, among others, in the hydromineral found that adenosine was indeed the first step of catecholamine balance of the organism by favouring capable of dramatically modifying synthesis) by each intermediate product water reabsorption by the kidney. Its pituicyte shape from a flat and fusiform of the synthetic chain. output is primarily regulated by the aspect to a shrunken cell body electrical activity of magnocellular surrounded by long processes, a Recently, we have obtained evidence in neurones. During dehydration, for phenomenon called stellation (Rosso et support of yet another type of negative example, the firing of these neurones is al. 2002a). We are currently in the feedback involving a crosstalk between increased via activation of peripheral, process of verifying whether this also the neuronal and glial components of central and intrinsic osmoreceptors occurs in vivo. Subsequently, we the neurohypophysis (Rosso et al. sensing a rise in plasma osmolarity (see discovered that vasopressin was able to 2004). This gland comprises primarily Bourque et al. 1994 for review). At the reverse stellation, bringing pituicytes three functional entities: the axon neurohypophysial level, this increased back to their basal shape (Fig. 1; Rosso terminals of the hypothalamic activity propagates to vasopressinergic et al. 2002b). If ATP and vasopressin magnocellular neurones that synthesize axon terminals whose secretory vesicles are coreleased within the pituicyte and secrete the hormones vasopressin release their content into the blood. environment, what could be the net and oxytocin; pituicytes (the glial component); and blood vessels, which drain the hormones from the sites of release and allow them to reach their cellular targets through the general circulation. Here we describe how vasopressin may regulate its own output by acting upon pituicytes, the specialized astrocytes of the neurohypophysis.

Since the late 1950s, work from several laboratories has suggested that pituicytes might be involved in the regulation of hormone secretion from the neurohypophysis. This idea was generated by electron microscopy studies indicating profound Figure 1. Time-dependent (in min) changes in pituicyte morphology elicited by vasopressin (VP; 10 nM) and morphological changes in pituicytes revealed by F-actin immunofluorescence. The cells were initially stellate due to the presence of adenosine (Ado; during physiological states that involve 10 µM) in the culture medium. FEATURES PN 31 effect of two simultaneous signals full action of the hormone. Thereafter, having opposite actions? Our when the water balance begins to be provisional hypothesis is that during the restored and the need for vasopressin initial stages of secretion vasopressin subsides, a powerful negative feedback receptors are internalized – and thus can be activated via taurine-induced non-functional – due to the high blockade of release, which may help concentrations of vasopressin ‘seen’ by terminate the action of vasopressin and the cells. This idea is borne out both by prevent water overload. previous observations in various cell types and by our own unpublished data. Most of these results were obtained in Therefore, we believe that the vitro. If they are confirmed in vivo, they purinergic effect (chemically both ATP Figure 2. Selective concentration of taurine in will provide another example for the pericellular protrusions 1 min after 10 nM vasopressin and adenosine are purine compounds) use of a negative feedback mechanism application. Pseudo colours represent varying in the control of the organism’s initially prevails, and that adenosine- fluorescence intensity of anti-taurine antibody from low induced stellation in vitro corresponds (blue) to high (red) levels (from Rosso et al. 2004). secretions. Furthermore, such a to the morphological changes observed mechanism would represent a novel in vivo upon activation of the levels in the isolated neurohypophysis, physiological role for neuron/glia hypothalamo-neurohypophysial system. which is consistent with the need to interactions. It should be noted that stellation keep vasopressin levels low under these Lia Rosso reversal can be elicited by very low conditions. We, in turn, have Brigitta Peteri-Brunbäck vasopressin concentrations (EC ~0.1 50 demonstrated that vasopressin itself is Jean-Marc Mienville nM), so that following hormone capable of inducing pituicytes to CNRS – UMR 6548, Laboratoire de Physiologie clearance and/or adenosine breakdown, release taurine, again suggesting a Cellulaire et Moléculaire vasopressin might be able to negatively negative feedback mechanism for self- Université de Nice-Sophia Antipolis, Nice, France feedback on its own secretion by limitation of secretion (Rosso et al. returning pituicytes to their resting 2004). morphology. References An intriguing aspect of vasopressin’s Bourque CW, Oliet SH & Richard D (1994). Osmoreceptors, osmoreception, and osmoregulation. Front Neuroendocrinol 15, 231- A second component of this putative action on pituicytes was the formation 274. negative feedback consists of the ability of cellular protrusions intensely stained Hatton GI (1988). Pituicytes, glia and control of terminal secretion. J of vasopressin to release taurine from for taurine (Fig. 2). The nature and Exp Biol 139, 67-79. pituicytes. Taurine is known as an physiological role of these protrusions Hussy N (2002). Glial cells in the hypothalamo-neurohypophysial ubiquitous osmolyte in the regulation of remain to be established. One important system: key elements of the regulation of neuronal electrical and secretory activity. Prog Brain Res 139, 95-112. cell volume, but its role in the functional parameter of the taurine- Rosso L, Peteri-Brunbäck B, Vouret-Craviari V, Deroanne C, Troadec neurohypophysis has more of a releasing effect of vasopressin is that it J-D, Thirion S, Van Obberghen-Schilling E & Mienville J-M (2002a). signalling nature, inasmuch as it is prevented in hypertonic conditions. RhoA inhibition is a key step in pituicyte stellation induced by A1-type inhibits vasopressin release by Therefore, one can reason that during adenosine receptor activation. Glia 38, 351-362. activating strychnine-sensitive glycine the initial stages of hormone demand, Rosso L, Peteri-Brunbäck B, Vouret-Craviari V, Deroanne C, Van Obberghen-Schilling E & Mienville J-M (2002b). Vasopressin and receptors located on neurohypophysial e.g. during dehydration, vasopressin oxytocin reverse adenosine-induced pituicyte stellation via calcium- terminals (reviewed by Hussy, 2002). will be unable to release taurine dependent activation of Cdc42. Eur J Neurosci 16, 2324-2332. Here, the physiological significance is because of the hyperosmotic Rosso L, Peteri-Brunbäck B, Poujeol P, Hussy N & Mienville J-M straightforward given the fact that environment of the neurohypophysis, (2004). Vasopressin-induced taurine efflux from rat pituicytes: a potential negative feedback for hormone secretion. J Physiol 554, hypotonic shocks increase taurine thereby allowing unimpeded output and 731-742.

Journals for Iraq says that almost none of the professors A Cambridge student, wounded while in Iraq’s universities have visited a filming in Baghdad in July, has research university in their field outside launched a drive to help restock Iraq’s Iraq. In many classes textbooks are universities with books and journals. either non-existent or more than 20 Raeid Jewad, a PhD student at Darwin years old and access to contemporary College, hopes that people will donate books and journals is therefore a journals, reference books, dictionaries priority. Anyone who might be able to and works of literature. He says that help can contact Raeid Jewad by email the British Council will handle the at: [email protected] shipping of books and journals and he has discussed their distribution within Right: Maggie Leggett (the Society’s Deputy Iraq with the Ministry of Higher Executive Secretary) married James Relf (former Education and Scientific Research. Society facilities, grants and membership officer) on John Agresto, who heads the Ministry, 27 February. 32 PN FEATURES

Qualia and private languages Denis Noble explains the ‘private language argument’, where philosophy and neurobiology meet head-on

Naively, I respond initially by saying ME: Yes, I certainly see that, but I ‘don’t be silly, we both learnt what it don’t see why that entitles you to say means to refer to black and white at our that you have a private world that I mother’s knee!’1 can’t know about.

Denis Noble YOU: Oh yes, of course, but that is not YOU: Look, this is getting what I mean. When we learnt at our exasperating. Obviously I am not Since writing the Foreword to mother’s knee, I thought we were all referring to my neurons, or my blood Philosophical Foundations of looking at the same things and must see flow changes, or anything else of a Neuroscience (Bennett & Hacker, them in the same way. Since then I’ve physical nature. I am referring to these 2003), I have been asked to explain the read some philosophy and neuroscience sensory experiences that I have. You ‘private language argument’ in terms and I can’t for the life of me see how know, they even have a name now. more familiar to scientists than the anyone else, even our mother, could People call them ‘qualia’.2 You must dense tomes of Wittgensteinian know what I am seeing when I look at also have them. Just look at one of philosophy. a black font. My experiences are inside those letters on the page. There is a me, inside my head, in my brain, and black on white quale there! The argument lies at the core of a set of no-one else can see them. I may see the philosophical puzzles, so one can world completely differently from the ME: So you have become a dualist? encounter it in various guises. Let’s way you see it. You think there is something there that take an example of such a puzzle. The is not physical? protagonists in my story are called ME ME: Oh dear, you’ve become quite a and YOU for convenience and all you solipsist recently. I also feel like that YOU: Oh no, not at all! These things need to know about them is that they sometimes. Don’t worry, it will pass. are created by my neuronal processes, have the same mother. Let’s have a curry together. perhaps in a sense they are my neuronal processes – or at least what it While I am writing this document, I YOU: No, no, it won’t pass, you really feels like to have them. We are not look closely at the print. I note that it don’t understand. I am serious. I am going back to Cartesian dualism. I am is black and the page is white. So, I tell me. You are you. You can’t know what not supposing a soul that interacts with you that I am currently writing this I experience in my own private world. my brain. In fact I just think that I am with a black font on a white my brain. And my brain creates these background. You reply that, yes, you ME: Where on earth is that? experiences that I see, feel, hear.3 understand what I have told you, but you nevertheless have a nagging doubt. YOU: Don’t play games with me. You ME: I thought that these experiences can’t see inside my head. were created in the same world that You express this by saying ‘How do both you and I live in, which is why I you know that I see black, or white, as ME: Well, actually, I can. We can was puzzled about reference to ‘your you do? Perhaps, what I see when I record from your neurons, scan your private world’. receive your email is what you would brain for blood flow changes, and many see as blue on pink, or green on other things. We would find inside YOU: Well, yes, that’s sort of true. But ultramarine, or any one of millions of your head much the same stuff that you I am not referring to the things in the possible combinations, including would find in mine. world itself. I am referring to the colours that perhaps you have never quality of the sensations I have when I seen! The only restriction is that the YOU: Yes, I know that. I don’t think I see the world. That’s why they are form of the relations between my am different because I am made called qualia. perceived colours and yours must be differently – though equally obviously such that we always agree on what to we are not physically identical. It’s just ME: So, wait a minute. When you look call what we see. We use the same that … well, I am me, and you are you. at a black font, you think that there is names, but we may see differently.’ Don’t you see? not only the black font itself but also

1 Actually, this move is not as naïve as it may initially appear – see the denouement of this story.

2 This term was originally introduced by 20th century philosophers to refer to the ‘qualitative character of experience’. The singular is ‘quale’.

3 This stage of the argument could have been the departure point for another version of the private language puzzle. The protagonist, ME, could have asked what on earth the ‘I’ was doing in this sentence. It would take another version of the dialogue to explore the problems created by this way of speaking about the relationship between the self and the brain. This illustrates the point that there is a set of puzzles here that are all inter-related by various versions of the private language argument. FEATURES PN 33 something else that is inside your head? don’t refer to it as ‘kcalb’ for example. – qualia – for which we can have no Actually, (Oh dear, this is getting experimental evidence; that you YOU: Yes, you’ve got it. I wish I could muddling!), I don’t think I use any communicate with yourself about have put it that way myself. words at all – I certainly don’t need to. seeing these qualia in a language that is either not a language, or just the same ME: But that’s just another form of ME: So, this language is neither a language you use to tell me ‘I see dualism. Why do you need to suppose different language and, possibly, it isn’t black’; that we are not talking about that there is anything inside your head even a language at all? there being anything inside your head other than the neuronal processes that other than material substances (neurons, occur when you see a black font? YOU: Well it’s certainly not a language blood vessels) of the same kind that I as we learnt at our mother’s knee. But, have in my head; so where is the YOU: No, wait a minute. I don’t think look, it’s very simple really. I see black. science in this ‘private language’ stuff? these qualia are a different sort of I know I see black. I remind myself that substance, something ethereal and this is the same kind of quale that I YOU: OK. I agree that I am expressing ghostly. have experienced before. If I must put a particular philosophical view of the it into words, I suppose I would tell world. But I also think that there are ME: But that’s just what it sounds like myself ‘I am seeing black’. some kinds of philosophical beliefs that to me! Tell me this. You are a scientist. are necessary for us to conduct You think that your brain is a material ME: And when you say that to yourself scientific investigation. How could I thing, though fiendishly complex. What you also tell yourself that you are possibly study the brain-mind problem possible experiment can we perform communicating something different if I didn’t think there were qualia that will confirm whether or not these from what you would communicate to formed as a result of neuronal things that you call qualia exist? me when you say to me ‘I see black?’ processes of a certain kind? Goodness me, this is the greatest challenge for ……… long silence ……. YOU: Yes. neuroscience! You can’t convince me that this is all a wild goose chase! ME: Well? ME: So what is it that is different? ME: Maybe not, but if I am right then YOU: Well, it’s not like that. As I said YOU: I’ve already told you. It is the you don’t even have a problem. In the before, you can’t know what I description of the quale, not the font sense we are talking about here, there is experience, so I can’t tell you. itself – it’s how I see it. no mind-brain problem. ME: ‘So, what do you do? Do you, as it ME: But we don’t know that they exist. YOU: What?! were, tell yourself – perform a kind of We have no way of conducting an self-talk? How do you compare your experiment to see whether they exist. ME: Well, it’s up to you. If you think own experiences? So why do you need to refer to qualia? there is a problem, then there is a Why not go back to when we learnt problem, but perhaps the problem is the YOU: Of course, that’s easy. I know language at our mother’s knee? When way you are thinking, not a problem for what I mean when I refer to black and I we saw black, mother said ‘that is science. You are proposing to can remember what it was like. So, in a black’, so we both got to know that that investigate a phenomenon for which we sense, I can tell myself ‘this is black’. is what it is called. Isn’t that simple? can have no experimental evidence; Moreover, we could only do that that requires a language that is private – ME: But you can’t tell me?! You must because all three of us looked at the which is a contradiction in terms; have a private language. same pictures in the same book. That’s languages are for communication – and how we came to use the same language. which leads to a modern form of YOU: Well, if you want to put it that If we had been French we would have way, I suppose I do. But everyone does. dualism which I would suggest is alien called it ‘noir’, if we were Japanese we to what science can seek to know about would have learnt to say ‘kuroi’, but we ……… different long silence ……. us as human beings. would still have ended up being able to YOU: Don’t you? do all that anyone ever can do to YOU: I think we had better have that communicate what they see when they curry. You will have to tell me what ME: Well, I am not sure about this. Tell see black. Mother didn’t ask us whether you see as the relation between mental me, where did you learn this ‘private we could see any strange qualia! and physical events! language’? Does it have the same words as our language? YOU: No, but she didn’t know any Denis Noble science. University Laboratory of Physiology, Oxford, UK YOU: Well, I hadn’t thought much about that. Yes, I suppose it does. At ME: Hey wait a minute. This is not Reference least, when I tell myself that I see science! We seem to have agreed that Bennett MR. & Hacker PMS (2003). Philosophical Foundations of black, I don’t invent a new word. I what you are talking about is something Neuroscience. Blackwell Publishing, Oxford. 34 PN INTERNATIONAL NEWS

Clinical physiology in Warsaw Who we are and where we come from

medical education were institutionally separated and independent postgraduate medical schools were created throughout the communist bloc. MCPE came into being in 1967 as a result of a secession of a part of the Warsaw Medical School. The idée fixée of its founders was that it should function and be organized in exactly the same Andrzej Beresewicz (left) and Bohdan Lewartowski, hosts of the joint workshop with the Physiological Society in way as other medical schools in Poland Warsaw in May (although the students to be taught were already graduates of medical schools). This spring (13-16 May 2004) the all physicians specializing in cardiology This meant that in addition to various Physiological Society is organizing a and cardio surgery (some 150 medical departments, which were workshop in cardiovascular physiology persons/year). For several years we also already available, new basic science entitled ‘Signal transduction in cardio- taught cardiovascular physiology to departments, including physiology, had vascular system’. The meeting is undergraduate medical students. Apart to be organized from scratch. primarily intended for young scientists from every-day teaching and research, Fortunately enough, MCPE was given a from Central and Eastern European MCPE is also responsible for brand new building, initially designed countries. It will be held in Warsaw, organization and supervision of the as a city hospital, to house its and its Polish co-organizer is the national system of medical theoretical departments. Physiology got Department of Clinical Physiology specialization by physicians, dentists, an almost completely equipped (DCP) of the Medical Centre of and pharmacists. operation theatre, a completely empty Postgraduate Education (MCPE), an space originally built for a nephrology independent academic medical school Historically, medical schools in Poland ward (nine rooms), and, with one providing postgraduate education. were always parts of universities. Only exception, employed very young and Outlined below is a brief profile of our after the Second World War did Poland completely inexperienced staff. department and its history. and other Eastern Block countries adopted a so-called ‘progressive’ Bohdan Lewartowski was appointed to DCP is one of the few laboratories in pattern of organisation of their organize and head DCP (till 1999, when Poland dealing with cardiac academic education, which meant replaced by Andrzej Beresewicz). At (patho)physiology. Our current teaching separating faculties of theology, that time he was a young (38) obligations include 6-7 two-week medicine, agriculture and others from enthusiastic MD, PhD (docent) trained courses per year (lectures, seminars and their mother-universities and in physiology. He had just returned laboratory demonstrations on establishing independent educational home after a 6 month stay in the ‘physiological bases of clinical institutions. Subsequently, Department of Experimental cardiology’), which are obligatory for undergraduate and postgraduate Cardiology, University of Amsterdam headed by Dirk Durer, and was fascinated by different electrophysiological techniques, including microelectrode recording. It was perhaps this fascination, the availability of surgery facilities, and the team’s medical background that determined DCP’s scientific interests for subsequent decades. The main topics of the research were: (i) electrophysiology of ischemic heart and cellular mechanisms of cardiac arrhythmias (the topic now abandoned); (ii) the mechanics and energetics of the left ventricle, particularly during Figure 1. Microelectrode recording of cellular action potentials of the left ventricle of the in situ dog heart regional ischemia (experiments on fibrillating due to occlusion of coronary artery. Reproduced from Czarnecka M, Lewartowski B, Prokopczuk A open-chest dog hearts, also abandoned (1973). Acta Physiol Pol 24, 331-337. now); (iii) excitation-contraction INTERNATIONAL NEWS/AURORA MISSION PN 35 coupling under physiological and made it everybody’s desire to earn pathological conditions (role of money outside the country and spend it Why British physiologists sarcoplasmic reticulum, mechanism of at home. Scientists in Poland were initiation and maintenance of the tonic offered such a possibility. Now that the should be part of the component of cardiomyocyte exchange rates are no longer so contraction, ECC in heart failure); (iv) attractive, it is medical practice and/or European Space mechanisms of myocardial the pharmaceutical industry, rather than ischemia/reperfusion injury in the western laboratories, that offer the most Programme – and what is models of isolated rat and guinea-pig favourable earning possibilities. stopping us heart (the role of free radicals, endothelium, nitric oxide and local It was always a rule in DCP that inflammation); and (v) mechanisms of everyone who got his PhD degree was myocardial and endothelial protection entitled to spend 1-2 years in a foreign by ischemic preconditioning. It is lab. Most of us did so (in Holland, hardly surprising then that the first Switzerland, Germany, Sweden, the original research papers from DCP USA, Canada and the UK). This described effects of propranolol on enabled a transfer of new techniques to cellular action potentials in rabbit DCP (e.g. microelectrodes, isolation of cardiomyocytes, voltage clamp papillary muscle and dog Purkinje A major reason why many of us believe passionately fibres and an original method of technique, intracellular calcium in human space physiology is that it is such a sexy ventricular wall tension measurement in measurements) and allowed us to subject - Michael Rennie dog hearts. To the best of our maintain contacts with the western The European Space Agency has made knowledge, the first published science and scientists. Probably because a commitment to a manned mission to microelectrode recordings of of these personal contacts, the Mars using the Moon as a staging post. ventricular fibrillation from in situ heart European Society for Clinical Named the ‘Aurora Mission’, it signals (Fig. 1) were done in DCF. Actually, till Investigation invited DCP to organize a a new dawn in the confidence of the late 90s, DCF was the only lab in 3 day workshop for young European European scientists and technologists Poland in which cardiac cellular clinicians interested in basic cardiology to take part in this great endeavour – potentials/currents were recorded. (1978). Sadly many DCP alumni took the exploration of our solar system. Altogether, approximately 100 original the opportunity of being outside the Unfortunately, Britain so far has had papers in peer-reviewed journals and ‘iron curtain’ and sooner or later little to offer, mainly because our numerous review articles and book emigrated, mostly to the USA. financial contribution to the European chapters have been published from Currently, there are perhaps more Space Agency is almost entirely based DCF since its foundation. former members of DCP working upon those physical sciences and abroad than in Poland. This accounts technologies for which the government The current staff of DCP consists of for a ‘generation gap’ (deficit of can see a quick market return, i.e. two professors (one emeritus with part- middle-generation scientists) in a satellite navigation systems, mobile time appointment), three senior majority of scientific institutions in phones, and earth survey activities assistants (all of whom obtained their Poland (and perhaps other post- including meteorology. In fact Britain PhD in DCP in last 3 years), three communist countries) and is among the puts in less money than Belgium, an younger assistants (PhD students), and most serious threats for our future astonishing difference when the GNPs two technicians. Initially most of the scientific development. of the two countries are considered. staff were MDs (which is important when it comes to the postgraduate Poland and nine other countries are to A few of us have been attempting to teaching of physicians). However, in join the European Union on 1 May, persuade Lord Sainsbury and others, the last decade the proportion of MDs 2004. There are many, often unrealistic, including Ian Halliday, head of PPARC on the staff has systematically fallen expectations related to this event. One, which takes the lead in space matters due to poor wages in basic sciences. we believe realistic, is that the easiest (he is fond of saying ‘Everything above The salaries were always small but it part of the job will be to create ‘the 100 km is ours’) that there are was a sort of ‘travelling privilege’ European Union in Science’. The sufficient major benefits to biology in rather than salaries that eventually initiative of the Physiological Society general, and certainly to human attracted young people to the basic in organising and sponsoring meetings physiology, for us to be profitably sciences. Poland was unique among the like that in Warsaw seems to support involved. The space shuttle dealt a Soviet Union satellites in that Poles this notion. dreadful blow to the idea of manned were allowed to travel abroad, and space exploration, but Ian Crawford of young scientists with a PhD could take Bohdan Lewartowski UCL has recently argued (Astronomy & post-doc positions in western Andrzej Beresewicz Geophysics, 45, 2.28-2.29, (2004),* laboratories. In those days the Department of Clinical Physiology, Medical Centre of given that UK participation in Aurora extremely favourable exchange rates Postgraduate Education, Warsaw, Poland is to be ‘science driven’, many 36 PN FEATURES scientific disciplines, including the people for relatively long periods of problems of inappropriate lifestyle. planetary sciences would benefit from time lying in beds in Toulouse or Many of these people will suffer the presence of human explorers on the Cologne, where the current long and muscle and bone wasting for which surfaces of the Moon and Mars. There short term bed rest studies have been there are currently no good effective, is no substitute for human beings for conducted. affordable drugs. Furthermore, there are space exploration because of human no good animal models of sarcopenia versatility, especially the ability to But why should Britain be involved? and osteopenia, so human make on the spot decisions and The answer to this is that we have a pathophysiological research is really serendipitous discoveries not foreseen long tradition of high quality human the only game in town. Although the in advance. Imagine if the descendants physiology (not that human physiology remits of the BBSRC and the MRC are of Captain Fitzroy and Charles Darwin is the only consideration – there are so tightly drawn as to exclude the had been on Beagle II – the dog which many studies to be done in tissue funding of human physiological did not bark in the night. Possibly, all culture in space which would be research using space as a tool, it seems they would have needed to do to restore invaluable for understanding to those of us who are concerned about communications was simply substitute angiogenesis, osteogenesis, stem cell this that were some new government a new circuit card for the one that was physiology, etc.). In particular there are money to be found for Aurora (PPARC malfunctioning. a number of physiologists interested in are seeking £25 million), and if part sarcopenia and osteopenia and the were earmarked for human space However, to get to space there are biomechanics of the musculoskeletal biology, as it ought to be, it would be many problems to be overcome. The system, such as Geoffrey Goldspink best administered through the MRC and problem of solar radiation, many fold and Steve Harrridge at University the BBSRC, who I am sure would be greater than on earth, is severe, but College London, Marco Narici at the very happy to do the job. there are also pathophysiological Manchester Metropolitan University problems with wasting of muscle and and at Nottingham my colleague Paul Of course, another major reason why bone. We know from studies of Russian Greenhaff and myself who together many of us believe passionately in astronauts that a relatively short sojourn possess a portfolio of tools which in its human space physiology is that it is in space, 6 months to a year, results in breadth has great potential for such a sexy subject. There can be few massive loss of bone and muscle mass, understanding the changes which occur schoolchildren or university students and indeed also of cardiac muscle mass. with zero gravity. Such expertise is who would not be very interested in the Returning astronauts from the estimated probably unmatched in Europe. If we biomedical problems of muscle and 3 year round trip to Mars could well could gain access to astronauts bone wasting in space. We need a have lost more than half of their bone spending some time on the flagship project in Britain to re- and muscle in the process. This is International Space Station, possibly as invigorate the interest of our youth in essentially a medical technological part of their training for Aurora, I science. What better than Aurora? And problem but it will depend upon the suggest that, using modern, molecular what better than British involvement in identification of good counter measures biological and genetic techniques, we Aurora? Why not a British scientist like which can be used in space. could rapidly discover the nature of the Kevin Fong, an astrophysicist-turned gravity sensor. Having done so, the doctor at University College London, Modern techniques for discovering pay-off would be enormous in terms of who has done much to promote the idea alterations of gene expression using identification of pharmacological of a British involvement in space, as gene chip technology and proteomics targets for drug ligands which could Britain’s first space physician? are more likely to succeed if studies are stimulate bone and muscle growth here done on astronauts before and after a on earth. We already have seen a huge Michael J Rennie relatively short duration trip to, say, the expansion in the proportion of our School of Biomedical Sciences, University of International Space Station than by population over 65, and this proportion Nottingham, Derby studying relatively large numbers of will grow exponentially, because of the *http://www.star.ucl.ac.uk/~iac/AG_Moon_Mars.pdf EDITORIA L BOARDS PN 37

The Journal of Physiology

The Editorial Board meeting held in The Journal of Physiology April was one of the largest ever, with Symposium 35 Editors attending. It was the first A Symposium in honour of the late meeting for Richard Fitzpatrick (he Eberhard H Buhl will take place on eventually made his first meeting after Friday, 10 September 2004 at the a couple of earlier attempts) and Caryl University of Leeds, Leeds, UK. Hill, new Editors from the antipodes. Entitled ‘Structure/function correlates in neurons and networks’, speakers As usual, there was much discussion will include: about how to get The Journal's impact factor over the magic number of 5. Brian Robertson (The Journal of Physiology There are no easy answers to this apart Editorial Board) Peter Somogyi (Oxford, UK) from only accepting the best papers, Vincenzo Crunelli (Cardiff, Wales, UK) which hopefully will be well cited. Ole Paulson (Oxford, UK) Perhaps we should do as one journal William Large (above) has been appointed as Chair- John O’Keefe (London, UK) was rumoured to do, i.e. insist that all Elect to take over from Stewart Sage as Chair of the Hannah Monyer (Heidelberg, Germany) authors include an extra reference to a Editorial Board of The Journal of Physiology in July Roger D Traub (Brooklyn, NY, USA) Journal paper, or maybe not. 2005. Istvan Mody (Los Angeles, CA, USA) Katalyn Halasy (Budapest, Hungary) The Journal has recently trialed a press Gianmaria Maccaferri (Chicago, IL, USA) release system through the new Gabor Tamas (Szeged, Hungary) publisher. This resulted in an article in Ivan Soltesz (Irvine, CA, USA) Alex Thomson (London, UK) New Scientist and two other online Kai Kaila (Helsinki, Finland) journals. With the success of this first Stuart Cobb (Glasgow, Scotland, UK) attempt we are enthusiastic to spot André Fisahn (Stockholm, Sweden) more potential papers. Roland Jones (Bristol, UK) Miles A Whittington (Leeds, UK) The Board briefly discussed the publishing of Meetings abstracts as part Full details are available at of The Journal. Over the lifetime of http://www.jphysiol.org The Journal, these abstracts have been Caroline Rae (left) and Melanie Parkin pictured at their ‘farewell’ meal with staff from the Publications Office at published as part of a normal volume Brown’s restaurant in Cambridge but it was in 1991 that they were first published as separate Proceedings Publications Office issues. Since January 2003 they are At the end of February the Publications only published online on the Society Office said a sad farewell to Melanie web site. There are mixed feelings Parkin and Caroline Rae (pictured about whether they should continue to above), who had worked as Distribution be part of The Journal and I am sure Assistants for 6 years and 3 years this will be discussed by Members respectively. The Bench>Press before any decision will be made. manuscript submission database, introduced by The Journal in It was useful having Liz Marchant from November 2001, has streamlined the Blackwell at the meeting, who is the handling of manuscripts to the point main contact now for both journals. She where there was insufficient work to justify the employment of four staff in informed us that 63% of our 2003 Eberhard Buhl’s work will be celebrated at The Journal subscribers had taken out a subscription the Distribution Office. Melanie and of Physiology symposium in his honour at the this year, which is apparently a Caroline therefore accepted the University of Leeds. Untilf his untimely death last year perfectly acceptable percentage for this Society’s offer of voluntary redundancy at the age of just 43, Eberhard was Head of the School of Biomedical Sciences at Leeds and his time of the year. in the hope of pursuing more research attracted major research grants totalling over demanding positions elsewhere. Dave £2 million, from sources such as the MRC, the We were saddened to hear of the death Gunn left in May. Based in the Wellcome Trust, German medical research charities of two ex-Editors, Tony Edwards (who Cambridge office, Dave has been and the National Institutes of Health in the USA. also served as Press Secretary and responsible for IT since joining the Eberhard (pictured above) was a member of The Chairman) and Hirosi Kuriyama. Society in 1996. Our very best wishes Journal’s Editorial Board from 2001-2003 and in 2002 for a happy future go with all three of was appointed to membership of the Neuroscience Jill Berriman them. Board of the MRC. 38 PN AFFILIATE NEWS/IMAGES OF GLASGOW

UK grad courses Glasgow: art and culture Don’t put off that course, advises Laura Blackburn – it may be a pleasant surprise! represented a different party involved in the crisis, and it quickly became clear how difficult it can be to sort out problems on a large scale, especially when people’s livelihoods are involved.

I found the most intriguing part of the Laura Blackburn course filling in questionnaires that looked at personality types and team There is a great deal of emphasis on the roles. It was interesting to see how wide range of skills needed by research different types interact and how scientists today. Knowing which understanding these differences makes transferable skills are important and interacting with people you might not relevant can sometimes leave you get on with easier. feeling a bit bewildered. Courses run by the UK Grad Programme, which are We also had sessions on ways to plan highly recommended by the research your time and work, and on dealing councils, are a good place to start, but with any problems that arise in the deciding which one to go on can in course of research. Most importantly, I itself be rather daunting. I have to met other research students and found admit that I am guilty of putting it off that, unsurprisingly, everyone has for as long as possible. I had visions of difficulties at some point but the vast being stuck on a windy hillside in the majority can be easily solved. Lake District with an unknown group of people, trying to make a raft with There are longer residential courses on two fairy liquid bottles and a ball of offer, with a wide range of training, string that would get us home down the which may even involve a touch of raft rapids to safety, and all in the name of building! Funding is available from the self improvement! research councils, so if you were not sure about attending a course, maybe The truth was less dramatic and a you could give one a try. Information is pleasant surprise. I opted for a 2 day available at: http://www.grad.ac.uk. non-residential course closer to home, which was useful for my PhD and Laura Blackburn taught me a few things about myself Department of Zoology, University of Cambridge which I didn’t know (and confirmed many things that I did!). The emphasis Thanks to those of you that voted for a was on team working, discovering how new Affiliate representative. I am you interact as an individual with other please to announce that Patricia de people, and also how you form a part of Winter will replace Catherine the team as a whole. Bleasedale. She is a mature student at Birkbeck, University of London, and After some very brief introductions we about to complete her PhD. She has were launched into the exercises. The been an Affiliate Member for 3 years first was to design, build and market a and is keen to promote the involvement gadget that could solve a world of young physiologists in shaping the problem. This was an opportunity to be Society's future. When Rob Wykes, the innovative and imaginative, aided by other Affiliate representative, steps the contents of an envelope containing down this September Helen Taylor will the Blue Peter basics – string, paper, take his place. Helen is a PhD student (Photographs by Prem Kumar) tape, plastic cups and coat hangers. at Sheffield, and will work to improve See p. 40 for Glasgow personalities communication with Society Affiliates. We then moved on to a case study, looking at an environmental problem Affiliate Members – don’t forget to send in your contributions for Physiology and how it could be solved. Each group News to Laura at [email protected] LETTERS TO THE EDITOR PN 39

is referring to. More predictable is the The questions relating to reversal of What’s new in anaesthesia motor response to a tetanic stimulus; a NMBAs are seen as very important by Dear Editor, strong sustained contraction with no a number of leading academic While Bill Winlow’s description of the evidence of ‘fade’ denotes full return of anaesthetists on both sides of the use of neuromuscular blockers in neuromuscular transmission – not Atlantic. In addition, several drug anaesthesia (Physiology News, 54, 11) exactly a new observation! companies (without whom anaesthesia would have interested your readers as would not be possible in the first place) physiologists, as potential patients it While it is nice to have the advances in have invested substantially in trying to must have been rather alarming. one’s trade described in the Society’s develop rapid offset NMBAs or binding Fortunately, much of what he said bears publications I was somewhat alarmed agents that rapidly reverse little relation to clinical practice. by Bill Winlow’s interpretations. neuromuscular blockage. Of course, Postoperative residual curarisation Should any of our Members go into development of such drugs would also (PORC) was a major problem with the hospital for surgery they can be assured help to increase the efficiency of traditional long acting non-depolarising that under anaesthesia all their surgeons, anaesthetists and nursing muscle relaxants (d-tubocurarine, physiological functions will be staff, because patients would have to alcuronium, pancuronium – all of them monitored properly and they will not be spend less time in the recovery room excreted in the urine) particularly in woken up until they can breathe following anaesthesia. There is patients with impaired renal function. adequately. I would not like them to therefore a clear economic argument in With their slow offset one could not think they were at the mercy of a bunch favour of such drugs, but only if they attempt to reverse them (with of pharmacological cowboys. do not harm the patient. neostigmine) for at least 40-50 minutes after administration. To do so led to Iain Campbell With regard to Dr Campbell’s thoughts Department of Anaesthesia, Wythenshawe Hospital, on the ‘train of four’ ratio, I gather that only partial recovery of neuromuscular Manchester, UK function and impaired movement and this is still used more commonly than ventilation. Postoperative residual Bill Winlow replies: tetanic stimulation in the UK. I do curarisation is not a problem with the I agree with much of what Iain agree with him that not giving a patient modern neuromuscular blockers Campbell says and I very much hope neostigmine could result in inadequate (vecuronium, atracurium and that I have not unduly alarmed any ventilation. However, if a compound mivacurium). They have much shorter fellow physiologists who might be was available that could reverse the durations of action, can be easily contemplating surgery in the near effects of NMBAs more rapidly and reversed within 30 minutes of future. However, I feel that I must with no side effects, wouldn’t that be administration and have a far more address some of his comments. Before well worth having in the rapid offset, so it is not always doing that, let me make my own pharmacological armamentarium? necessary to reverse their action with position clear. I am a medical writer neostigmine. These drugs are also Bill Winlow and as part of my job I am managing Medical Writer, Prime Medica Ltd, Knutsford, Cheshire metabolised in the blood stream editor of aspects in anesthesia, which (atracurium, mivacurium) or in the has an independent editorial board and liver/excreted in the bile (vecuronium) is supported by an unrestricted so renal function is not a major educational grant from Organon. ‘Emeritus’ membership? consideration. Dear Editor, There is still clearly an issue relating to I am long retired and unable to get to Most of us do not rely on subjective post-operative residual curarization meetings readily, but I still much value assessments of muscle strength (head amongst anaesthetists, and serious my (reduced-rate) membership of the lift, hand grip etc) to assess recovery worries about antagonism of Society, reading Physiology News with but monitor neuromuscular function neuromuscular blockade and reversal of pleasure and interest, and at least using a nerve stimulator. The ‘train of the effects of neuromuscular blocking scanning the Meeting programmes. I’m four’ is a research technique for those agents (NMBAs). These were topics happy with the present system – though interested in these drugs, but is almost that were discussed in both the not all might feel able to afford the impossible to use properly in routine European and American societies of subscription – but I’d urge caution in clinical practice. It is possible to anaesthesiologists in 2003. I note that adopting the word ‘Emeritus’ observe the ‘train of four’ or test its the issues are again being raised this (Physiology News, 54, 33). When I strength manually, but four brisk and year in a number of sessions in both the retired from a Professorship at Cardiff apparently equal responses can still World Congress of Anaesthesiologists the word was added to my title, and at denote only a partial return of in Paris in April and at the European first I supposed it indicated some neuromuscular transmission. To wake a Society in Lisbon in June. Much of the special, albeit modest, worthiness. patient up in these circumstances discussion centres on restoration of However, I see from the dictionary that without giving neostigmine may well voluntary control of the airway after it merely meant that I had duly served result in inadequate ventilation and it surgery, as I made clear in my original my time. As it comes from the past could be that this is what Bill Winlow article. participle of emereri and is ‘not 40 PN LETTERS TO THE EDITOR naturalized’, you would need to alter field of ‘philosophy of mind’ is likely letter from Olga Hudlicka (Physiology the ending as appropriate for the to depend partly upon the study of News, 54, p 40) came as somewhat of a feminine or plural forms, which might interacting hierarchical systems. surprise to me, although I welcome it be a nuisance. since, as the recent former holder of the After I had completed my academic Bowman Chair of Physiology and Head Vernon R Pickles studies, I became especially interested of the Department, I had been fighting 65 Yarnells Hill, Oxford, UK in what is now called ‘bioethics’. long and hard to retain physiology as Some of the chief problems in this field an identifiable discipline. Professor On retirement are ones in which I had already become Hudlicka’s article makes some good Dear Editor, involved as a pharmacologist, e.g. points and has an important message. When I retired in 1980, I had just therapeutic trials, drug abuse. My Before dealing with these I feel it turned 60 and could have remained in training in philosophy has given me a necessary to provide a little bit of the employment at Otago University for broader view of these problems than I recent history of events. another 5 years as Professor of had earlier, one result being a booklet Pharmacology. However, that did not entitled Drugs and the Law in New Some 7 years ago the University appeal to me because I had found that Zealand. decided to do away with departments being departmental head gave me too and set up divisions within the various little time for research. I therefore My chief reason for mentioning these schools that are now part of super- became a student again, proceeding personal details is to indicate that faculties. So physiology was not alone first to a BA and then to an MA in colleagues approaching retirement from in losing its department status. philosophy. a university are likely to have a wider However, instead of being moved en range of choices than between merely bloc into a division of basic medical One source of my interest in easing off and becoming a ‘social sciences or life sciences, as I had philosophy was Karl Popper, who scientist’ (as described so delightfully strongly argued, physiology was taught in New Zealand during the by Vivian Abrahams (Physiology News, divided up, with the bulk of individuals 1940s and who had been brought down 54, 33) and getting into something so being placed in medical sciences (with from Canterbury to give a course of radically different that little use can be medicine, surgery, anaesthetics, lectures at Otago. Incidentally, these so made of one’s existing expertise. geriatrics and cardiology) and the rest impressed Jack Eccles, the Professor of in a division of neuroscience (which Physiology, that he became one of When I first considered changing the included pharmacology, neurology, Popper’s first influential advocates. It direction of my studies, I assumed from neurosurgery and psychiatry). Thus, to dawned on me that philosophy was a national statistics that I would have to use Austin Elliott’s description, we field in which I could work without do this by age 60 if I was to expect were ‘atomized’. The rationale for needing any equipment, research having at least another good 10 years. doing this was, and still is, unclear, assistance or even an office at the Expectation of life has since improved particularly when you know that University. Thanks to the development to the extent that someone who retires several of us might be considered as of such instruments as the word wholly at 65 may be in for a long, dull neuroscientists as well as processor and the laser printer, I am future. cardiovascular scientists. So where now home-based, though I still attend would our natural place be? We relevant sessions at the University. Fred Fastier thought of ourselves as physiologists Emeritus Professor of Pharmacology University of Otago, Dunedin, New Zealand and being in one location meant we Another inducement was realizing that could interact with like minded some of my special knowledge could scientists. The apparent sidelining of be put to use. For instance, much that Whither physiology? physiology was further emphasised by has been written about ‘the philosophy Dear Editor, the unwillingness to recruit new high of science’ deals largely with the The debate about physiology in modern calibre scientific staff to replace some physical sciences. Relatively little science has been opened up somewhat distinguished colleagues, despite my attention has been given to the complex dramatically by the startling images in vigorous requests. However, it appears multilevel explanations that are so the last magazine of the empty space that things are changing, since much a feature of physiology. created by the demolition of the somewhat surprisingly, and out of the However, that situation is changing building once housing the Department blue, some 6 months after my departure with the realization that progress in the of Physiology in Birmingham. The the Dean has announced he has

Glasgow personalities From far left: Jeremy Ward, Chris Fry and colleagues; Susan Wray and Society Meetings Secretary Bridget Lumb; Hans Hultborn and Alan North LETTERS TO THE EDITOR PN 41 appointed Janice Marshall to the change? It is still not clear to me what They are much more able to respond to Headship of the Department of advantages have been gained by new developments because they retain Physiology. Janice is well qualified for amalgamation. Has it really been a mixture of expertise. For example, the post, and I wish her well in what driven by Research Assessment the trend to appoint molecular will be a very difficult task. So things Exercise? The reorganisation in biologists and cell signallers is leading may be changing, although the Birmingham was not, since the basic to a worrying loss of skills in department is greatly downsized, now scientists in the Division of integrative and systems physiology. It less than 50 per cent the size it was in Neuroscience (mainly pharmacologists is the latter we need to exploit the great 1997, with the remaining staff scattered and physiologists) were returned as part discoveries of the genomic era. throughout the very large medical of the RAE with several of the John Coote school building. Is this then a retreat physiologists from the Division of University of Birmingham from the original objective since we Medical Science. seem to have come full circle? In a way it is, because it is the beginning of Has amalgamation resulted in new Determinants of human a recognition that physiology is collaborations? It is probably too early important as a subject in its own right. to know, but my own experience here exercise performance So let’s consider why this should be. in Birmingham is that very active Dear Editor, collaboration was already occurring Much has been written about the post The study of how living systems work with other departments and this was not genomic era. The reality is that we are is a crucial part of biology and is as reflected in the restructuring. For only just beginning to understand how fundamental as physics, chemistry and example, my own research involved to integrate genomic datasets with mathematics in understanding the scientists from cardiovascular medicine, physiologically relevant measures. In natural world. Hence there are various pharmacology, biochemistry and sport recent editions of Physiology News (53, types of physiologist: plant, and exercise science. Apart from the p 7; 54, p 8), the functional limitations invertebrate, comparative, sport and first of these the others are all in and adaptability of skeletal muscle have exercise, etc. as well as physiologists in different divisions or schools. So we been discussed in separate articles. the medical sciences. These exist as work with whom we will, not because strong research groups or even as we are close neighbours. The From the society’s point of view this is departments in some universities, and department gave us the feeling of unquestionably an important topic as it in all cases a critical mass is essential belonging to something where our impacts on disease burden, government to prosecute the research at the highest voice could be heard and a sense of economics (from sick-pay to tax international level. This is true in common purpose. The way we went revenue from betting on sport) and on medical schools as well, but here there about our work, the way we thought the aspirations of individuals (athletic are further critical factors that argue for was as physiologists, not performance). The question is how a clear identity (probably as a pharmacologists or biochemists, etc. much do we really know about the department). A good grasp of To me there is a clear difference. We determinants of human performance? physiology is essential for practitioners need the opportunity to talk with You can’t look at a group of athletes in the health sciences, including physiologists as part of our home and pick the best by eye, you can’t medicine. It provides a way of thinking department, but to also ensure that even analyse the style of an athlete and about biological systems in the context ‘over the fence’ interaction with our define the likelihood of success of disease and furthermore ensures a colleagues in other disciplines is made (consider the atypical running styles of thorough understanding of the basic easy. So am I arguing for maintaining Michael Johnson or Paula Radcliffe). principles for the best practice of the the status quo? Not really. I am happy It would be easy to presume that profession. Therefore those who teach with conglomerates of departments performance determinants for achieving should have a broad understanding of providing identity of disciplines is a gold medal at the 200 m track event the subject even though their research maintained. I can understand that represent an extrapolation from the expertise is in a tiny portion of it. Too university managers consider the larger requirements for catching a departing often I come across complaints that groupings more financially viable, but bus, when you are ‘running’ late for new staff recruited for their research to don’t let us be deceived into believing work. Certainly, they both require a enhance RAE scores have little it leads to better research or to degree of muscular strength and power, knowledge of the physiology (or for stimulating the acquisition of new likewise they also require a finite level that matter anatomy, biochemistry and skills. The proven way of doing the of commitment and motivation (how pharmacology) outside their research latter is via the grant-giving bodies. much do you want that medal or how area, yet they are expected to supervise Our projects won’t get funded unless much do you really want to catch the and tutor in the new-style small group we move with the times. teaching. I wonder how much bus to work?). misinformation is imparted which has So I make a plea for retaining to be undone later. In general, the old departments that represent fundamental The truth is that the majority of detailed style structure of departments of basic disciplines like physiology even though scientific studies of skeletal muscle disciplines avoided this. So why they may be within a conglomerate. performance are more likely to have 42 PN LETTERS TO THE EDITOR been carried out in the group of ‘bus- sample) represented on the DNA chip. physiological parameters from the high catchers’ than potential Olympic From the 24 subjects that undertook the responding group. Much to our surprise medallists. Observations that a high supervised training, the top eight the low responder subjects failed to level of endurance performance cannot subjects (in terms of improved demonstrate a significant modulation of be continued when muscle glycogen performance and enhanced aerobic genes related to muscle angiogenesis stores are depleted (Bergstrom et al. capacity) were utilised for the gene and cell differentiation. For one 1967) appears a robust observation; array experiments. Approximately example, a gene involved in new blood however, does the availability of 1,000 genes were modulated vessel growth was nine fold up- glycogen really determine the gold sufficiently to be detected by the regulated in our high responder group medallist from the silver medallist in microarray (this is likely to be an and unchanged in our low responder the marathon? Likewise, enhancing incomplete list as there are inherent group. This data allows us to consider a muscle phosphocreatine stores would limitations to such methods). Stringent number of interesting questions. Do the appear to potentiate sprinting statistical analysis allowed us to successful athletes represent a subgroup performance (Casey et al. 1996), for identify ~140 genes most modulated at of motivated individuals that are lucky reasons that still remain to be fully a level of 1.5 fold up or down enough to adapt substantially to a explained. Yet do we have clear regulated. Since the muscle samples training stimulus? Alternatively, and evidence that first past the post had were taken 24 hours after the last perhaps of greater interest, are people greater PCr reserves? We also know training session these genes did not who suffer from frailty, cachexia or that under pathophysiological reflect the acute response to exercise metabolic diseases related to muscle, conditions, the route for ATP but rather a ‘stably’ altered expression those subjects that are unlucky enough resynthesis can impact on the rate of level. not to respond to everyday physical muscle fatigue developments (Timmons activity? et al. 1997), but is this really the Interestingly, the majority of the genes primary limitation in the exercise most modulated in the young healthy It is very clear from our study and the intolerant patient? The simple answer to male volunteers did not relate to classic data emerging from other research these questions is that we do not yet skeletal muscle processes (such as groups that the determinants of have the evidence to make such energy metabolism) but rather reflected adaptability of human skeletal muscle specific conclusions. the remodelling of the extracellular are complex and still poorly What assumptions can we therefore environment. This would be presumed characterised. The observation that rely on? A valid assumption that may to facilitate such process as failure to adapt to aerobic exercise in a determine muscle performance under angiogenesis, matrix remodelling and robust fashion is reflected in a failure to any circumstance is the concept of muscle stem cell activation. Indeed, we activate groups of genes, locally in the adaptability. If one fails to adapt to were able to establish that the muscle tissue, is somewhat surprising repeated exposure to muscular work, continued genomic response to aerobic given that the overriding dogma would then no amount of inherited ability will exercise, in adapting human skeletal still favour a central limitation to take you to the top of your chosen muscle generated clusters of changes in aerobic performance. The results of this sport. Likewise, the decline in muscular gene transcripts that went in the study indicate, however, that the real performance with age or disease may opposite direction from changes determinants of success during this simply reflect a failure to maintain the observed in animal models of skeletal summer’s Olympics may have more to status quo, due to lack of biological muscle atrophy (Lecker et al. 2004) do with how the athlete has responded response to daily activity. If we are to This gave us confidence that we were to years of preparation, than any understand the basis for muscle looking at a genuine and functionally quantitative physiological process adaptability, then a reasonable place to coordinated pattern of gene responses. during the event. start would be to capture the global The next question was to establish if James A Timmons1,2 any of the ‘groups’ of genes reflected genomic response to endurance Carl Johan Sundberg2 training. Certainly, this should be processes critical to muscle adaptation. 1Centre for Genomics and Bioinformatics & relevant for cardiovascular-metabolic 2Department of Physiology and Pharmacology, disease prevention, physical To address this question, we decided to Karolinska Institute, Stockholm, Sweden rehabilitation and aspects of athletic examine some selected genes in the References performance. eight subjects which demonstrated the Bergstrom J, Hermansen L, Hultman E, Saltin B (1967). Diet, poorest adaptation to aerobic training. muscle glycogen and physical performance. Acta Physiol Scand 71, 140-150. In a recent study, we examined changes These subjects had been identified Casey A, Constantin-Teodosiu D, Howell S, Hultman E, Greenhaff in muscle gene expression following 6 because despite undergoing the same PL (1996). Creatine ingestion favorably affects performance and muscle metabolism during maximal exercise in humans. Am J weeks of aerobic cycle training using relative training load, under supervised Physiol 271, E31-37. the Affymetrix gene array platform. At conditions, they were ‘unable’ to Lecker SH et al. (2004). Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB the time of our study we had 66,000 demonstrate substantial improvements Journal 18, 39-51. probe sets (segments of genes that will in aerobic capacity, cardiovascular Timmons JA, Poucher SM, Constantin-Teodosiu D, Macdonald IA, Greenhaff PL (1997) Metabolic responses from rest to steady state bind to and recognise if that particular adaptation or exercise performance. determine contractile function in ischemic skeletal muscle. Am J gene is expressed in our biological These subjects did not differ at baseline Physiol 273, E233-238. SOCIETY NEWS PN 43

scientific advice to Parliament and they Voices of the Future 2004 offer 3 month internships to PhD Emily Ferenczi and Andrew students in science who have an interest in writing for Parliament. This is an Murton report on the Royal opportunity that Young Affiliate Society of Chemistry’s Members of the Physiological Society annual opportunity for young may want to explore. The day’s scientists to meet UK programme concluded with the opportunity to attend a formal meeting politicians of the Science and Technology Select Noon, Monday 22 March, 2004. Over Committee where we heard evidence 150 young enthusiastic scientists from the new Director General for mingled over salmon sandwiches and Emily Ferenczi - encouraged to realise that highly Higher Education, Sir Alan Wilson. Thai prawns at Portcullis House in qualified, influential individuals shared her concerns Westminster. There were regarding the position of science in society The event opened my eyes to the inner undergraduates, PhD students, post- workings of Parliament. It was docs; physicists, chemists, medics; A panel of seven members of the Select encouraging to realise that highly Brits, Australians, Americans, Committee of Science and Technology qualified, influential individuals share Germans… the diversity was striking. took our questions regarding the my concerns and those of other young Once the preliminary socialising was decisions and dilemmas we face as scientists regarding the position of over, we settled down to the serious young scientists embarking upon our science in our society. It is through purpose of our visit to the House of careers. Despite the diversity of fields events such as these, where the voices Commons. Voices of the Future is an and ages represented, several themes of of the public can be heard, that annual event organised by the Royal shared concern were prominent. The important issues in science can be Society of Chemistry. It provides young inadequacy of mathematics and science addressed and eventually changes can scientists with an opportunity to meet education in schools was addressed, be made for the better. and question UK politicians who are including the decline in number and Emily Ferenczi involved in science and technology quality of school science experiments. Oxford University Medical School policy, funding and administration. The point was also raised that too great an emphasis is put on the teaching of Parliament is often accused of being We were welcomed by Ian Gibson MP, facts and knowledge as opposed the out of touch with reality, and this Chair of the House of Commons Select process of thinking and learning. accusation extends into the field of Committee on Science and Technology. Higher education issues were discussed, science. In an attempt to dispel this As a scientist himself, his vision is that such as the debate on tuition fees and myth, the Government, in association science will adopt an expanding role in the under-representation of women in with the Royal Society of Chemistry, the maintenance of the stable economy science at university. Of universal hold an annual event entitled Voices of of this country over the next 10 years. concern were postgraduate issues such the Future. He encouraged us to engage with the as the ‘brain drain’, where talented media and with Parliament in order to young British scientists are drawn away This year’s event was held within the put science in its rightful place. from science in the UK by higher amazingly designed and engineered salaries abroad (such as in the USA) or Portcullis House, Westminster. Over The Secretary of State for Education in other career paths. 150 young scientists from a diverse mix and Skills, Charles Clarke, delivered a of disciplines attended the event. clear and encouraging speech, The afternoon continued with an emphasising two main points. Firstly, entertaining and informative address by After a brief welcome by the Chief he believes that an important battle has Lord May, President of the Royal Executive of the Royal Society of already been won: raising Government Society. He emphasised that the Chemistry, David Giachardi, we were awareness of the need to give greater growing scientific and manufacturing privileged with the company of Charles priority to science education. He feels capacity in the developing world has Clarke MP. After speaking on his main that this commitment to investment in increased the need not only for objective, altering the public’s science education is reflected in the ‘knowledge creation’ in the UK through perception of science, he opened the recent budget. Secondly, the battle still teaching and research, but also the need floor to questions, which he answered to be won is in the implementation of to exploit this knowledge by carrying it in the usual political fashion. this commitment through changes in into the market place for ‘wealth the curriculum, encouraging relations creation.’ A short break later and we were between teachers and scientists, capital introduced to the members of the Select investment in school infrastructure and We were introduced to a representative Committee of Science and Technology, the provision of incentives for science of the Parliamentary Office of Science chaired by Ian Gibson MP. They teaching. and Technology. The office provides answered competently any outstanding 44 PN SOCIETY NEWS questions that the audience had. With extremely pleased when we won a prize (Government Advisor), Derek Bell the Committee being formed from the sponsored by the Institute of Physics, (Association for Science Education), three main political parties, it was who are very supportive of this work John Coggins (Scottish Education), quickly evident that there was no and of women in science issues in John Holman (York), Caroline Hurran hidden agenda in their responses. The general. The prize money will be used (Wellcome Trust), Jane Lewis (GSK members, all of whom have established to launch and disseminate the Charter. Academic Liaison Manager), Colin scientific backgrounds, appeared Affiliate Members will be aware that in Miles (BBSRC), Michael Reiss (Inst of genuinely concerned at the current state early April I advertised for some Education) and the President and of affairs within science in the UK. The scientists in the early stage of their Treasurer of the BSF. The willingness committee reassured the audience that careers to join the group to help of senior figures to become involved is they were aware of the issues, including progress the Charter and other women an indication of both the importance of specifically wages, career progression in science activities. I was amazed at the issue and the respect with which the and stability, and that they were being the response, with more than 10 Federation is held. addressed. Affiliates volunteering in the first 24 hours. We now have a large working European Liaison Group Finally, a speech by Royal Society party and an even bigger virtual At the second meeting of the President, Lord May. It was good to discussion list. I think the level of the Federation’s European Liaison Group know that the Government is trying to response – which was not just from UK in February, which included delegates support the international reputation of based Affiliates – demonstrates the size from the Royal Society, MRC and British led research, and more of the problem. I hope that the Charter BBSRC, the Wellcome Trust, the ABPI, importantly, the scientists behind it! will prove to be a useful document, by Academy of Medical Sciences and highlighting the issues, sharing good medical research charities (the Andrew Murton practice and encouraging Institutions to BioIndustry Association has since University of Nottingham be more supportive of female joined) there was a strong feeling that researchers. the case has not yet been made for a European Research Council. The Deputy Executive Secretary Maggie Leggett meeting recommended that the on winning team biomedical sciences should be lobbying If you would like to join the women in for research to be funded on a science virtual discussion list, please European scale only where this adds email me at [email protected]. definite value over national funding.

Other items discussed included the revision of the Directive regulating animal research; implementation of the The first few months of 2004 have been Clinical Trials Directive in the UK; an exciting time for the Federation. Commissioner Busquin’s call for a Maggie Leggett and Louise Archer collect the ATHENA Those of you who look at the website European medical research forum: and award at a Royal Society reception. (www.bsf.ac.uk) will be aware that the EU Chemicals policy. Delegates agreed letter to the Prime Minister regarding to bring to the next meeting the Last year I attended the launch of a the honours system controversy recommendations of their organisations Scientific Women’s Academic Network received a response with a hand written on priorities for the UK Presidency of (‘SWAN’) at London Metropolitan note from Tony Blair saying ‘As you the Commission in 2005. University. The audience at the launch know, I am fully supportive of the suggested that there should be more scientific community on this issue. But Survey on awareness of a coordination between these networks I can’t help what’s in the press!’ There joint Code of Practice for and other women in science activities is also to be a full enquiry into the commissioned research in universities. To this end the manager honours system, which at time of DEFRA, BBSRC, NERC and the Food of the London Metropolitan SWAN, writing is on-going. Other recent Standards Agency (FSA) intend to Louise Archer, formed a working party successes include: introduce a code of practice for to develop a charter for women in research that they commission from science. Louise and I led this project, Working Party on Sustaining June 2004. In the case of BBSRC and which involved significant consultation Biosciences in the UK NERC the code will apply only to their and redrafting. It became clear that the The recommendation to set up this research institutes, but for DEFRA and approach was both novel and welcomed working party came from the members the FSA it will apply to university labs by other stakeholders. We decided to meeting. As a first step the Federation as well. The Federation has published a enter it for an ATHENA award, and has invited selected stakeholders to a survey showing that workers in were asked to present the work at an working dinner. Almost all the invitees research institutes are well aware of the event held at the Royal Society. I was accepted, including Derek Burke need for enhanced quality assurance SOCIETY NEWS PN 45 procedures to be introduced by June, achieved since it was formed, and much whereas those in university labs are is promised”. The support of the Pfizer Prizes generally ill-informed and unready. The Research Councils is welcomed; this Federation considers that it is move should pave the way for future unsustainable for there to be different collaboration. standards of quality audit required for research institutes and university labs, Future events and within university labs for work The Federation’s workshop at the commissioned by BBSRC and DEFRA, British Association Festival of Science for instance. A report has been sent to will be held on 9 September (see the Heads of Quality Audit of the separate advertisement). There will be a Pfizer Prize winner Derek Scott participating research funders, and we symposium on the commercialisation of await a reply. bioscience on 12 October at the Royal I was very pleased to receive the Pfizer Society. There will also be three careers prize for my oral presentation entitled Education Committee conferences, at King’s College London ‘cGMP/PKG II-dependent inhibition of An article I wrote based on last (6 Nov), Leeds University (20 Nov) 2+ a pH-dependent Zn -evoked October’s Education Colloquium was and Glasgow University (27 Nov). electrogenic transport pathway in published in the Spring edition of human intestinal Caco-2 epithelia’ Science in Parliament, the Journal of Maggie Leggett given at the Society’s 2003 Manchester the Parliamentary and Scientific Meeting. This was part of our group’s Committee. It appeared alongside work investigating electrogenic articles by the Higher Education transport processes evoked by iron and Minister Alan Johnson and science zinc in Caco-2 cells, and whether they curriculum adviser John Holman. The Archives correlate with changes in metal Federation has also recently To complete its set of Experimental transporter expression. I have recently collaborated with the Independent Physiology (formerly The Quarterly taken up a post as Teaching Fellow in newspaper to produce a supplement on Journal of Experimental Physiology) Biomedical Sciences at the University the Biosciences. It is a useful guide to and for archiving purposes, the of Aberdeen, where I can combine university education and careers in the Publications Office is looking for teaching physiology with my research. life sciences. copies of volumes prior to 1986 (volumes 1-70). Derek Scott £20,000 donation from the College of Life Sciences and Medicine, University of Aberdeen Research Councils If you have any of these volumes The MRC has made a one-off donation which you no longer need, please to the Federation of £10,000, BBSRC contact Emma Ward £7,000, and NERC £3000, to cover a 3- ([email protected]). Any postage year period. Colin Blakemore wrote “I costs involved will be reimbursed. have a very high regard for the Federation and its work; much has been

Sohag Saleh (above), from St George’s Hospital Medical School, also won a Pfizer Prize at the Society’s Manchester Meeting for a talk entitled ‘The characterisation of voltage dependent currents and calcium activated chloride currents in the mouse portal vein’.

Lauren Mackenzie (above) from the Babraham Institute won the poster prize at the Cambridge Meeting for her poster ‘The spatial properties of calcium transients modulate contraction in rat atrial myocytes’. 46 PN UNBELIEVABLE!

apply their knowledge. Don’t get me wrong. I do think PBL is a good idea. Well, some of it. It puts knowledge into context, teaches self-motivated learning, etc. etc.

But I do get a sneaking suspicion that the bit where the tutor doesn’t have to know much – any? - human physiology is just a bit too convenient in an age The truth is out there – but where? where many physiology departments (if they are still called that) appoint and I don’t believe it myself. Can I, as a few of my junior colleagues seem to retain staff mainly on the basis of the working hospital doctor – and reader of realise that simply measuring a research money they generate, rather your magazine - pose you physiologists patient’s peak flow rate is no way of than their ability to teach. a question: monitoring them for impending respiratory failure due to muscular Yes, even the most RAE-ravaged Do you actually teach medical students weakness (as seen, for instance, in department will still be able to teach physiology these days? Guillain-Barre syndrome). (You have to (and get the money for teaching) monitor their vital capacity, which medical students, because a highly Yes, yes, I do realise that I sound like a better reflects the overall respiratory research-active yeast cell cycle cross between Victor Meldrew and a ‘muscle power’– another of those molecular biologist (to take just one caricature of an old-school consultant things physiologists used to teach back example) can still tutor a medical PBL surgeon. But is it really too much to ask in the old days). that the medical students understand at group. least a few important basic principles of Sorry? What’s that? It’s not the I don’t think so. You see – I believe whole body physiology before they are physiologists’ fault? there is something quietly going let loose on unsuspecting members of seriously wrong here. The way the public - and their colleagues? Ah yes – enter Problem Based Learning. government money is distributed does Please - at least the principles where not provide enough reward for good ignorance actually can get quite As my physiology colleagues in the teaching, which has given the dangerous on occasion. university never tire of reminding me, universities the wrong idea. Teaching the students teach themselves is neglected - unfortunately with I am sick and tired of hearing junior nowadays, and therefore the dangerous real-world consequences. doctors tell me: ‘This patient with a ‘facilitator’ does not actually need to gastrointestinal bleed is stable after know any human physiology at all. Will this ever change? Possibly. After fluid resuscitation’ on my ward round. I all, the students - soon to be charged am then presented with a patient who, Indeed, most of the medical students I three grand a year up front for their having had a litre of 5% dextrose meet on the wards call PBL ‘DIY university education - might actually solution intravenously, has a transiently Medicine’ (although I have heard it start demanding to be taught. ‘normal’ blood pressure. No mention of called much worse). Now there’s a nasty thought. But it the raging tachycardia, non-existent might just do your granny a favour if urine output, and obvious Personally I think that’s exactly where she ever needs to go into hospital. hypovolaemia. the problem lies. The author is a harassed doctor Another example: why do even middle Just look at those examples above. working in general medicine grade doctors stare back at me blankly They are all real situations I have seen, when I try to explain to them why the and there are many more, where it is inotropic drug Dobutamine tends to obvious that basic principles of human For more on this issue, see the letter lower a patient’s blood pressure? β - physiology hadn’t been understood. from John Coote on p. 39. adrenoreceptors, anyone ? Different types in various bits of the body ? I am sure my junior colleagues had Do Society Members think done their homework as students and physiologists - or physiology Is that really too much to ask? had read, copied out, PBL-discussed departments - should be responsible and even learnt the appropriate chapters for teaching this sort of stuff any And there is worse to come: respiratory in the recommended books. more? Or should clinical medicine physiology. I believe there is actually a Unfortunately, no one suitably qualified teach medical students their nice little easy-to-read book out on that seems to have been around to actually physiology? WRITE IN AND TELL one. Pocket-sized, even. Unfortunately, check whether they understood or could US WHAT YOU THINK. OBITUARIES PN 47

Gerald A Kerkut 1927 – 2004 Gerald Kerkut would have been successful in whichever profession he chose. He could have been a musician, a banker or studied medicine. In the event he selected reading natural sciences at Cambridge (1945-48), where he proved a first class student, receiving prizes from his college, Pembroke, as a mark of his success. Gerald remained at Cambridge within Zoology for his PhD (1948-51). This was the period when Sir James Gray was Head of Zoology and locomotion 1959. This played an important part in establish the metabolic role of the was a major research interest of the the foundation of the Medical School at sodium pump in the generation of the department. Gerald, selected, or was Southampton with its first intake of resting membrane potential ( reviewed given, the topic locomotion in starfish, students in 1971. From 1956 until his by Kerkut &York, 1971). Gerald which involved large amounts of cine retirement Gerald played a key role in enjoyed challenging accepted dogma photography of tube feet movement. the training of science undergraduates and this is beautifully illustrated in his Under the guidance of his supervisor, in physiology, biochemistry, inaugural lecture, The Missing Pieces, Eric Smith, Gerald set out to determine pharmacology and related areas. In delivered in 1968 (Kerkut, 1969). which of two theories was correct for 1966 Gerald became the second Gerald and Robert Meech developed an locomotion in Asterias rubens. The Professor of Physiology and electrode which measured intracellular choice was either ‘traction’ theory Biochemistry at Southampton and later chloride concentrations. Using where the foot extended, attached and served as Dean of Science, Chairman of identified snail neurones which were then contracted, pulling the animal the School of Biochemical and either excited or inhibited by along, or ‘lever’ theory where the foot Physiological Sciences and Head of the acetylcholine, they demonstrated that acts as a strut which can be used as a Department of Neurophysiology. In these two types of neurone contained lever to propel the animal along, as a terms of research Gerald decided that different concentrations of chloride, person uses their leg. Gerald slugs were not the ideal gastropod for showing that the ionic content of demonstrated that, depending on research. There were many species neurones could vary. circumstances, the starfish could use which were often difficult to identify both methods (Kerkut, 1953). and so he looked for an alternative Gerald also pioneered the idea that Interestingly, publishing in the same animal. He had been interested in the amino acids, viz glutamic acid, GABA journal volume are many great names work of Arvanitaki and Chalazonitis and glycine, could act as transmitters. in experimental biology including (1955) who had been recording from He selected various invertebrate nerve- Ramsay, Fatt, Hoyle, Wiersma, giant neurones in Aplysia. Gerald could muscle preparations, where Furshpan, Florey, Needham, Munro see a future in a simple model nervous acetylcholine was not the transmitter, to Fox, Pilgrim, Edney, Katz, Chapman, system where he could study the basic demonstrate the release of glutamate Trueman, Mitchison, Swann, Williams, properties of neurones and synapses. under experimental conditions. This Parry and Knight-Jones, most of whom However, he decided Aplysia was too complemented the elegant work of the were linked with Cambridge zoology. difficult to obtain and too expensive to Takeuchis (Takeuchi & Takeuchi 1964). use routinely in Southampton. He He was also very interested in the Having completed his PhD, Gerald selected another gastropod mollusc, the transport along axons and provided never returned to echinoderms. Instead, garden snail, Helix aspersa, and so evidence for fast transport of material with George Hughes, he began work on began a programme of research using down the axon and slow transport in electrical activity in slug ganglia in this and other model nervous systems the opposite direction. During this relation to osmotic strength. He which was to extend over the next 40 period there was controversy over extended these studies with Brian years. whether insect neurone cell bodies Taylor following his appointment to a could generate overshooting action lectureship in physiology and Gerald had a first class knowledge of potentials. With Robert Pitman, Gerald biochemistry at Southampton, the the scientific literature and during his demonstrated that at least some insect institution where he was to remain for first 12 years at Southampton applied neurones, the DUM cells, were capable the rest of his academic life. With this knowledge to a number of of generating action potentials. Kenneth Munday, Gerald helped to fundamental topics. An observation that establish the Department of Physiology cockroaches move faster when the After working for almost 30 years on and Biochemistry at Southampton in vessel they are in is cooled led him to invertebrate models Gerald turned his 48 PN OBITUARIES attention to isolated mammalian CNS Physiology was undoubtedly the journal During the 1950s and 1960s Gerald preparations and with Jeffrey Bagust Gerald achieved greatest pleasure from supported positive links with scientists developed an isolated spinal cord and will prove his finest editorial from the Soviet Union. In 1967 he preparation using 3-6 week old memorial. I remember how excited he attended the first international hamsters, mice and rats. Using the was when he came into the laboratory symposium on the Neurobiology of isolated cord, Gerald investigated the clutching the first number. In the late Invertebrates, held in Hungary and synaptic and non-synaptic components 1950s Gerald met Robert Maxwell who organized by his friend Janos Salanki. of dorsal horn field potentials. He was had founded Pergamon Press and the The Balaton Limnological Research particularly interested in the sensory two immediately formed a rapport. Institute of the Hungarian Academy of connections within the cord. While Maxwell liked many of Gerald’s ideas Sciences, Tihany, provided an ideal listing the advantages of in vitro for the publication of science and venue for the interchange of ideas preparations Gerald always agreed to publish a journal on between scientists from ‘east’ and acknowledged that one had to relate comparative biochemistry and ‘west’. such findings to the intact living animal physiology. The deal Gerald made with (Kerkut, 1989).This review was the Maxwell was an excellent example of Gerald enjoyed music, art and travel. opening chapter of a Festchrift held in Gerald’s business acumen. Instead of He regularly practised on his grand Gerald’s honour in 1988 and attended receiving a fee as editor, Gerald piano and derived great pleasure from by many of his former postgraduates. received a percentage of the profits listening to music. He had an extensive from Comparative Biochemistry and collection of art books and never lost Gerald will always be remembered for Physiology. Gerald also had productive the pleasure in buying a book, his record in the world of publishing, industrial links and was involved in the particularly if it was a bargain. In his both in terms of journals and books. He design and development of medical youth he spent several months studying always encouraged young scientists to equipment. art in Florence and Venice. Up until 5 publish and often assisted them by or 6 years ago, Gerald travelled widely, publishing their work in one of his In 1997 Gerald established a charitable particularly in the Americas and the Far journals. Early in his career he accepted trust for the support of physiological East. Gerald enjoyed teaching and the challenge to revise ‘BEPS’ research at Southampton. He had some interacting with both undergraduates (Borradaile, Eastham, Potts & interesting thoughts on the allocation of and postgraduates. Many will retain Saunders, The Invertebrata) which grant income and was always very enduring memories of his humour and appeared in 1958. He revised almost supportive of staff who failed to gain concerned interest in their welfare. the entire text himself, an indication of such income but who continued to do During his active research period he his breadth of knowledge of the animal good research which they then trained over 80 postgraduates, whose phyla. He simplified many of the published. He was particularly success will provide a lasting legacy to figures, making them much more supportive of the training of his memory. He will be fondly student friendly. This approach to postgraduate students. The trust will remembered by his many friends and teaching was also reflected in the represent another memorial to him. colleagues. quality of his lectures to students. It was always a pleasure to attend one of Gerald was a great advocate of new Robert J Walker Gerald’s lectures, even at 9.00 am. technologies and edited a book on the University of Southampton role of microcomputers in neuroscience Evolution was another topic which (Kerkut, 1985). In the last few years References always intrigued Gerald and in his book Gerald became increasingly interested Arvanitaki A & Chalazonitis N (1955). Potentiels d’activité du soma neuronique géant (Aplysia). Arch sci physiol 9, 115-144. The Implications of Evolution, Gerald in his web site (with the assistance of Borradaile LA, Eastham LES, Potts FA & Saunders JT (1958). In critically reviews basic assumptions Frank Goodwin) and wrote on a wide The Invertebrata, 3rd edn, ed. Kerkut GA, p 795. Cambridge and implications regarding the origins range of topics, not only in science but University Press, Cambridge, UK. of life and the inter-relationships of the in politics, student concerns, money Kerkut GA (1953). The forces exerted by the tube feet of the starfish invertebrates (Kerkut, 1960). This book and education. The web site during locomotion. J Exp Biol 30, 575-583. was one of a series of 55 volumes (www.soton.ac.uk/~gk/index.htm) Kerkut GA (1960). The Implications of Evolution, p 174. Pergamon Press, Oxford, UK. which Gerald edited on topics in pure proved amazingly popular, achieving Kerkut GA (1969). The Missing Pieces, p 15. University of and applied biology – zoology. For a over 60,000 hits per week. Southampton, Southampton, UK. period Gerald also had his own Kerkut GA (1985). Microcomputers; the revolution of our time. In publishing company, Scientechnica. Up until the mid 1970s Gerald Microcomputers in the Neurosciences, ed. Kerkut GA, pp 1-8. Oxford However, in terms of scientific journal regularly took part in scientific University Press, Oxford, UK. editing, his two greatest contributions meetings, always ready to ask a Kerkut GA (1989). Studying the isolated central nervous system; a searching question. To the loss of the report on 35 years: more inquisitive than acquisitive. Comp Biochem were Comparative Biochemistry and Physiol 93A, 9-24. Physiology, which he started in 1960, scientific community he then largely Kerkut GA &York B (1971). The Electrogenic Sodium Pump, pp 187. and Progress in Neurobiology, which withdrew from attending meetings but Scientechnica, Bristol, UK. he edited with John Phillis from 1973. continued to communicate through Takeuchi A & Takeuchi N (1964). The effect on crayfish muscle of Comparative Biochemistry and editorials and reviews in his journals. iontophoretically applied glutamate. J Physiol 170, 296-317. OBITUARIES PN 49

urea transport in the loop of Henle, but wonderful dinners for colleagues John Atherton Young Karl persuaded him to apply around the world. 1936 - 2004 micropuncture techniques to salivary glands. This was a pivotal decision. In Maynard Case December 1965 John presented his data University of Manchester at a Meeting of the Physiological Society held at the London Zoo, where they caught the attention of Arnold Graham Francis Baker Burgen, who sought John’s permission 1947 – 2004 to include the data in his keynote paper at an international conference on exocrine secretion in Birmingham, Alabama and also arranged for John to be invited as a plenary speaker. Thus, John’s career was launched. Thereafter, he quickly became recognised as an John Young, who died on 10 February authority on exocrine secretion and the 2004 after a long illness, was a undoubted authority on salivary towering figure in Australian secretion, which he remained until his physiology and in global exocrine dying day, as evidenced by nine ISI- physiology. After studies in medicine defined citation classics and nearly in Brisbane, John travelled to Sydney 5,000 citations in all. for doctoral training in renal physiology, followed by post-doctoral John’s original studies on salivary duct Graham Francis Baker passed away at studies in Berlin, before returning to function (in Berlin) and micropuncture the beginning of March at the early age Australia in 1966 to a Senior studies (in Sydney), laid the foundation of 56, having succumbed to a Lectureship in Physiology at Sydney for understanding salivary glands, while pancreatic tumour after several months University. Subsequently he was whole gland perfusion studies (some of illness. promoted to Professor and Head of through collaborations with myself and Department (in rotation with Liam Martin Steward) and Graham was born in 1947 and went to Burke), before becoming Dean of electrophysiological and Christ’s College, a grammar school in Medicine in 1989 and then Pro-Vice- microfluorometric studies (chiefly with Finchley, and then to Bedford College Chancellor for Health Sciences in 1996, David Cook) added greatly to our where, in 1969, he was one of the first a post he held until his retirement in knowledge of salivary secretory men to graduate from this erstwhile April 2003. processes. women’s college in physiology in spite of his severe hearing deficit, which Despite the increasing pressure of these John also strayed in other secretory rather cut him off from the cut and demanding posts, he remained organs, including the pancreas where thrust of normal conversation. He then committed to physiology research we also enjoyed a fruitful collaboration. went on to work with Wilfred Widdas throughout his 40 illustrious years at The Sydney-Manchester connection led for a PhD, the completion of which was Sydney University and until the day he to more than a dozen joint publications, delayed by the untimely death of his finally succumbed to acute myeloid including four papers in The Journal of father in 1972, also of pancreatic leukaemia. He had continuous Physiology and many communications disease. He completed his PhD in 1974 NHMRC support from 1962 until to the Society, some given by John and worked with me for a period of retirement, and never had a grant during his sabbatical in Manchester (in time at St Thomas’s and then with application turned down. 1981) and subsequent visits, and these Richard Naftalin at King’s College led to his election to the Society in London. In 1981 he was appointed John had a true appreciation of the finer 1982. lecturer at Bedford College and after things in life. Given the choice of post- the merger with Royal Holloway he doctoral studies in Berlin and Chapel John was not only an excellent scientist moved to Egham. Hill (and remember this was 1965) he but a true scholar who enjoyed chose Berlin, to study with Karl Ulrich. synthesising work into carefully crafted A popular and excellent teacher, I suspect the choice was heavily review articles and a superb monograph Graham had a good rapport with the influenced by the presence in West on the morphology of salivary glands, students and was well liked by all. Berlin alone of two opera houses, seven written with his anatomical colleague Everyone who knew him remarked on symphony orchestras, 30 theatres and Ernst van Lennep. He was also one of his exceptional kindness and numerous museums (John was not the most generous people I know, helpfulness to those who asked for his afraid to state that he had never kicked someone who gave unsparingly to the advice. He always dressed elegantly a football in his life). He arrived in countless students he trained and and was well known for wearing either Berlin with the expectation of studying counted it a real pleasure to host an orchid or rose in his buttonhole. 50 PN FEATURES

Graham was a very able series of student projects with took his MA (Cantab) and qualified experimentalist, well organized and had implications for the understanding of MRCS, LRCP following completion of an excellent knowledge of physiology asthma. These projects were cut short his clinical training at the Radcliffe in general and transport in particular. by his illness. Infirmary, Oxford. Although he worked independently on respiratory epithelium he continued As well as his ability as a physiologist, From 1943 to 1946 he became working with Wilfred Widdas on Graham had a great interest in Demonstrator and assistant Lecturer in human erythrocyte transport systems horticulture and for many years enjoyed Pathology and Bacteriology at Guy's throughout his career. Graham had fresh vegetables and flowers from his Hospital Medical School and, in 1947, great skill in translating Widdas’s three allotments. He won many prizes Lecturer in Physiology at UCL under theoretical ideas into practical for his horticultural skills at local Sir Lovatt Evans. experiments using self-built equipment. competitions and the City of London Professor Widdas freely admitted that it Flower Show. Graham was a keen In 1948 he settled on a career in was only through Graham’s practical orchid grower and also kept bees. He physiology and pharmacology joining skills that they were able to achieve was particularly adept in growing many the full time staff at the MRC most of the results in red cell transport. varieties of apples and he was most Ophthalmologic Research Unit in Judd pleased when be beat one of the landed Street, and later the MRC External Staff As Wilfred says one of Graham’s main gentry at a Royal Horticulture Society at the Royal College of Surgeons, being scientific contributions was the Show. promoted to Special Appointments discovery of the asymmetric action of Grade. In 1957 his research into 4,6 O-ethylidene-D-glucose in Graham married Petroulla (Petra) in prostaglandins led him into the inhibition of glucose transport first 1986. They had two children, a discovery of irin. presented to the Physiological Society daughter, Emma (16) and a son, Paul in 1973. He showed that the inside (15). In more relaxed moments he enjoyed transporter site had a very low affinity, making music, for he was an whereas the outside bound the sugar Malcolm Segal and Richard accomplished violinist. In later years he with relatively high affinity. His Naftalin became more interested in the physical interest in the asymmetry of the sugar King’s College London character of violins, particularly the transporter continued long after this - famous ones. His garden gave him one of the last papers he wrote was great joy and he loved to share his with M Kaloyianni in 1998 on the Nachman Ambache discoveries of special plants with his effects of ATP on phloretin affinity. 1917 – 2004 many friends. Richard Naftalin and Graham collaborated in a study of the affinity of He died of heart failure on 3 February, the inner face of the glucose leaving a wife and two children, one of transporter. They found that the whom is a professional pianist. affinity for glucose was variable depending on how it was measured, Desmond Greaves Lyminton, Hants high on entry but low on exit. Tony (This obituary is published with permission from the British Medical Carruthers who was working with Peter Journal (2004, 328, 960). Baker at the time and Graham and Richard working together came up with a neat structural explanation for these Hannelore Pawelzik findings. They suggested that a 1960-2004 vestibule at the inner surface of the transporter was a plausible explanation Hanna joined my group in the for the kinetic asymmetry of the Department of Physiology in 1996, transporter. The more recent work on Born in Egypt in 1917, Nachman having completed her PhD with Walter effects of ATP on glucose transport Ambache came to this country in 1929 Zieglgansberger in Munich and began support this explanation. for education at Peterborough Lodge dual intracellular recordings in School, London, Clifton College, hippocampal slices with parallel Graham in latter years developed an Bristol and Trinity College, Cambridge, pharmacology and anatomy. Despite interest in transport across the nasal gaining Major Scholarships and First severe illness that resulted in a major mucosa and from this he evolved a Class Honours. operation in 1997 and treatment for the number of techniques for studying the rest of her life, Hanna was an active human airways in vitro. He developed In 1939 he returned to Egypt to work in member of the group and of the an interest in the effect of air pollution Professor Anrep's department and Physiology Department at the Royal in the airways mucosa and with this he gain some experience of physiological Free. Her courage, kindness, home successfully completed an interesting research. On his return to the UK he made cakes and love of opera will be OBITUARIES/BOOK REVIEW PN 51 remembered for many years. The The full significance of the work she studies that she performed on the did will probably not be realised for Other Members deceased since our pharmacological profiles of the some time. Her findings are becoming last issue. We hope to carry some inhibitory connections made by increasingly topical since they link the full obituaries in a future issue of morphologically identified hippocampal actions of drugs that alter mood and Physiology News: interneurones demonstrated that each behavioural state to the functions of Anthony E Edwards, Hirosi class of interneurone acts via a specific specific sub-classes of interneurones. Kuriyama, D M Lewis and Leon sub-class of GABAA receptors. Leonidovich Voronin Tragically, having returned to Germany Alex Thomson after working with us for 7 years, School of Pharmacy Hannelore died suddenly last month. London University

The biology of human Mars would rapidly boil and die of solved, but solved with redundancy and survival: life and death in ebullism. adequate safety margins before this Big extreme environments Idea has a chance of becoming reality. At a time when many physiologists are Claude A Piantadosi. 2003, Oxford University Press, £24.95, 263 pp. worrying about whether their subject One example can suffice to show why ISBN 0 19 516501 2 still exists (just for the record, I have integrative physiology will always be never been among their number), it is necessary to make sense of the mass of Anyone who has camped overnight in refreshing to come across a book which data emerging from more restricted the high mountains knows that one of is completely rooted in classical, studies of individual tissues, cells or the small compensations for a cold and integrative, systems-level physiology membranes. Heatstroke is the cramped night is that you can boil the and which also demonstrates so clearly unfortunate consequence of our core water for your tea more quickly than both how important this approach is for body temperature rising by more than usual the next morning. Water boils at a understanding many practical problems about 5oC. The most serious effects are lower temperature at altitude because of interest, and how much more shock and multiple organ failure. less energy is needed for water to important work there is to be done at Interestingly, these effects are similar to evaporate as atmospheric pressure falls. this level, without ever having to those occurring in the setting of septic For example, at about 14,000 feet water trouble one’s head about DNA, shock, which are substantially mediated o boils at 88 C. What happens if you molecular substitution or single channel by the lipopolysaccharides of bacterial keep going up in a balloon or currents. endotoxin. It turns out that there is aeroplane? At an altitude of 62,800 feet indeed a connection between these two the atmospheric pressure falls to 47 In 20 short chapters, Piantadosi treats apparently rather different pathologies, mmHg and water boils at a temperature us to a masterful survey of the key since the plasma concentrations of o that may seem familiar, 37 C. That is, physiological problems facing humans lipopolysaccharides in heatstroke the fluids in an unprotected human in extreme environments, from deserts victims show large increases. Why? body will boil just from the heat of of sand to deserts of snow, from the Normally, bacterial endotoxins are metabolism. This piece of bad news is depths of the ocean to the depths of sequestered in the gut by tight junctions known as ebullism: the outer space. The physiological limits between intestinal epithelial cells. But dimensions of the body may suddenly applying to lack of food and water, to this mucosal barrier breaks down at hypothermia in air and in water, to heat increase and unless the pressure around about 42oC due to decreased blood flow stress, rapid ascent, hyper- and the body is rapidly normalised, and direct heat injury to the cells, microgravity are all discussed briefly unconsciousness follows within allowing endotoxin access to the blood but clearly, with many fascinating seconds and death soon afterwards. Not stream, with disastrous systemic examples. A strength of the book is the really surprising given that the major consequences. constituent of the human body is author’s lucid exposition of the undergoing a physical change of state. amazingly narrow limits which our The story of human environmental This altitude limit is known as the basic physiological makeup can physiology contains riveting tales of Armstrong line after its discoverer. withstand and his emphasis on the triumph and tragedy in extraordinary Interestingly, the air pressure at the many behavioural ways in which we circumstances, as well as great science. Armstrong line is about seven times strive to overcome these limits – a It is difficult to imagine a more higher than that on the surface of Mars, perfectly legitimate, and indeed vital, engaging way to interest neophytes in which gives some indication of just aspect of environmental physiology physiology or to restimulate a more how vicious the current Martian that has often been skated over. The general awareness of the importance environment is and how difficult it book closes with a topical chapter on and intellectual excitement of would be to get humans there and back weapons of mass destruction and integrative physiology. Piantadosi’s safely. Even if her oxygen supply was another on human prospects for book is a superb primer in the field and unaffected and she was protected from colonising space, which calmly deserves a very wide readership. the cold, an astronaut who suffered a discusses the many problems alongside suit depressurisation on the surface of ebullism which need not just to be John A Lee 52 PN NOTICEBOARD

FORTHCOMING PHYSIOLOGICAL ADVERSE REACTIONS TO DRUGS AND THE PHYSIOLOGICAL SOCIETY SOCIETY MEETINGS CHEMICALS: STUDIES FROM For further details please visit the Society’s web site MOLECULES TO MAN CHANGE OF ADDRESS (http://www.physoc.org) University of Liverpool, Liverpool, UK 9-10 September, 2004 The Physiological Society Administration Abstract submissions Joint meeting of the British Pharmacological and Toxicology Authors should submit their abstracts online. Full instructions will be Societies. Office has moved to: available on the Society’s website (http://www.physoc.org/) from the opening day of the abstract submission period. email: [email protected] PO Box 11319 Website: http://www.bps.ac.uk London WC1X 8WQ 2004 Cork: 1-3 September ION CHANNELS: FROM PHYSIOLOGY TO King’s College London: 18-20 December PATHOLOGY (Joint Meeting with the Chilean Physiological Society) Universidad de Sevilla Focused meetings 7-9 February, 2005 Noticeboard Newcastle upon Tyne: 22-23 July This International Workshop will focus on the general aspects of ion Notices for the Autumn 2004 issue of Physiology Nottingham: July channel molecular physiology and channelopathies. The meeting is News should reach the Publications Of fice by 7 June, Bristol: 4-5 September sponsored by the Physiological Society and intended for young 2004 ([email protected]). Oxford: 1-3 October scientists from the UK, Spain and Eastern European countries, though participants from other countries are also very welcome. Up Please note that whilst Members are welcome to to 40 applications will be accepted and preference will be given to advertise relevant event s in Physiology News and on applicants who will present a poster. Interested applicants should the Society s website, advertisement s via email will be 2005 submit a short cv and register online by 1 September, 2004. restricted to event s sponsored by the Physiological Seville, Spain 10 - 13 February Society. Sponsored symposia in association with the Spanish and Dutch Website: http://www.physoc.org/international/seville2005 Physiological Societies Bristol 20–22 July THE PHYSIOLOGICAL SOCIETY List of Meetings during 2004 IUPS 2005 – 35th CONGRESS OF THE UNIVERSITY OF NOTTINGHAM INTERNATIONAL UNION OF 12-13 July (Focused meeting) PHYSIOLOGICAL SCIENCES San Diego, CA, USA 31 March–5 April UNIVERSITY OF NEWCASTLE-UPON-TYNE 22-23 July (Thurs-Fri) (Focused meeting) IUPS 2005 is being organised by the six member societies of the US National Committee of the IUPS, the American Physiological Society, Opening date for receipt of abstracts 26 April the Society for Neuroscience, the Microcirculatory Society, the Closing date for receipt of abstracts 5 May Society of General Physiologists, the Biomedical Engineering Society and the Society for Integrative and Comparative Biology, under the auspices of the US National Academy of Sciences. UNIVERSITY COLLEGE CORK AND ANNUAL GENERAL MEETING Website: http://www.IUPS2005.org 1-3 September (Wed-Fri) Opening date for receipt of abstracts 7 June Closing date for receipt of abstracts 16 June YOUNG PHYSIOLOGISTS’ SYMPOSIA Channels to Networks UNIVERSITY OF BRISTOL University of Leeds September 2004 4-5 September (Sat-Sun) (Focused meeting) For further information contact Helen Garner Email: [email protected] UNIVERSITY OF OXFORD King's College London 1-3 October (Fri-Sun) (Focused meeting) 17 December 2004 Opening date for receipt of abstracts 5 July Joint with the Chilean Physiological Society Closing date for receipt of abstracts 14 July Theme free symposium, abstracts on all topics welcome For further information contact Charlotte Waters (KCL) Email: [email protected] KING’S COLLEGE LONDON or Paola Casanello (Chile) Email [email protected] 18-20 December (Sat-Mon) Joint meeting with the Chilean Physiological Society Further information about these events will be circulated via email and published on the website. Opening date for receipt of abstracts 20 September Closing date for receipt of abstracts 29 September