Featuring: PHYSIOLOGYNEWS Newcastle meeting spring 2003 | number 50 Tenerife meeting

Limbs in limbo pH phantoms – a physiological phenomenon?

Nitric oxide microsensors

An interview with Professor Robert Winston

A physiologist digresses about piping

Cannon’s peak – a challenge to Society members Discover more possibilities Time-lapse Recording

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Contributions and Queries Executive Editor Linda Rimmer Editorial 3 Tel: 01223 368713 Fax: 01223 312849 Newcastle meeting Email: [email protected] Welcome to the University of Newcastle Barry Argent 4 The Society web server: www.physoc.org Tenerife meeting Recollections from Tenerife 2003: a truly first joint meeting Magazine Editorial Board Rafael Alonso Solis 8 Editor Bill Winlow (Prime Medica, Knutsford) Deputy Editor Features Austin Elliott (University of Manchester) Limbs in limbo: the problem of targeting Keri Lee Page 12 Members pH phantoms – a physiological phenomenon? Christof Schwiening 15 John Lee (Rotherham General Hospital) Munir Hussain (University of Liverpool) Nitric oxide microsensors Roger Wadsworth 19 Keri Lee Page (University of Cambridge) Labouring Lord. An interview with Professor Robert Winston Bill Parry 21 Maggie Leggett (Physiological Society) A physiologist digresses about piping Geoffrey Walsh 24 Cannon’s peak – a challenge to Society members Bill Winlow 26 © 2003 The Physiological Society Affiliate News ISSN 1476-7996 Suffering for science Keri Lee Page 27 The Society permits the single copying of individual articles for private study or research. Letters to the Editor 29 For copying or reproduction for any other purpose, written permission must be sought from the Society. Society News Staff changes Dafydd Walters 33 Opinions expressed in articles and letters submitted by or commissioned from Members, International collaboration Dafydd Walters 33 Affiliates or outside bodies are not necessarily Speakers in schools database Maggie Leggett 34 those of the Society. RDS Annual General Meeting Maggie Leggett 34 The Physiological Society is registered in England Unbelievable! Mark Cain 35 as a company limited by guarantee, No 323575. British Association Festival of Science Maggie Leggett 36 Registered office: PO Box 11319, London WC1V 6YB. Registered Charity No 211585. Careers conferences Maggie Leggett 36 Physiological and pharmacological in vivo Printed by The Green Tree Press Limited techniques workshop Maggie Leggett 36 Women in science – what are the issues? Maggie Leggett 37 Science Engineering and Technology Prize Christopher Huang 37 Proceedings in 2003 38 Cover image New Cell to Man Maggie Leggett 38 Other Society News 38

Obituaries Michael de Burgh Daly Jennifer Angell-James 39 Michael de Burgh Daly Prize Lecture David Jordan 41 David Keynes Hill Andrew Huxley 42 Mary Pickford Geoffrey Walsh 43 Laurence Malcolm Ruth Payne 45 Stanislav Tuc˘ek Ann Silver 46 Eberhard Buhl 46 Phantoms in the machine? A visual reconstruction of Reginald James Whitney Ken Collins, Joe McGlade 47 figure 2 in Christof Schwiening’s article pH Book Reviews 48 phantoms – a physiological phenomenon? on p17. Noticeboard 51 PHYSIOLOGYNEWS Action Points Guidlines for contributors Affiliate Travel Grant Scheme: These guidelines are intended to assist The deadlines for receipt of applications during authors in writing their contributions and 2003 are the last day of March, May, July, to reduce the subsequent editing process. September and November. The Editorial Group of Physiology News tries to ensure that all articles are written in BSc Intercalated Bursaries: a journalistic style so that they have an The main deadline for receipt of applications is immediate interest value for a wide 30 June, 2003 (~10 awards), with a second readership and will be readable and deadline of 30 November, 2003 (~3 awards) for comprehensible to non-experts. In institutions where projects are not decided until particular, scientific articles should give a the course has begun. good overview of a field, rather than focus Membership applications: on the author’s own research. The deadlines for the receipt of Full Membership Format of articles application forms during 2003 are the last day The main message or question posed of March, June, September and December. should be introduced in the first paragraph. Change of address: The background for the topic should then Members should inform the Administration be established, leading up to the final Office of any changes of address, telephone, fax dénouement or conclusion. or email addresses. Length of articles Changes can be emailed to: [email protected] This will be determined by the subject matter and agreed between the contributor Forthcoming Scientific Meetings: and the commissioning editor. Articles will EDITORIAL EDITORIAL Dublin (8 – 10 July, 2003) vary in length from 500 to 2,000 words Abstract submission period 7 – 16 April, 2003 Submission of articles Manchester (10 – 12 September, 2003) Authors should submit text in the form of Joint meeting with the British Pharmacological a disk accompanied by a printout wherever Society possible. Use of disks reduces the risk of Abstract submission period 2 – 11 June, 2003 errors during retyping. It is helpful to give brief details of the computer, operating Cambridge (17 – 19 December, 2003) system and software package(s) used. Abstract submission period 15 – 24 September, 2003 Submission deadlines Please contact the Executive Editor in the Abstract submissions: Authors should submit Publications Office (see Contents page for their abstracts online. Full instructions will be details) for submission deadlines. Late available on the Society’s website submissions will be deferred to a (http://www.physoc.org/Meetings/future.html) from the subsequent issue. opening day of the abstract submission period Illustrations/author’s photographs Physiology News: Authors are encouraged to submit diagrams, Letters and articles and all other contributions drawings, photographs or other artwork to for inclusion in the Summer issue, No. 51, illustrate their articles or, if they cannot should reach the Publications Office by 12 provide these themselves, to suggest March, 2003 at the latest. appropriate illustrations. A photograph of the author(s) should also accompany Physiology News Online: submissions. Photographs may be colour Physiology News is now available on our website or black and white, prints or transparencies www.physoc.org or tiff files with a minimum resolution of 300 dpi. Electronic colour figures should be in CMYK mode.

References Authors are requested to keep the number of references to a minimum – preferably no more than two or three. Please cite all PH references in the style of The Journal of Physiology (see Instructions to Authors 2003, www.jphysiol.org)

Suggestions for articles Suggestions for future articles are welcome. Please contact the Executive Editor or a member of the Editorial Group of Physiology News (see Contents page for details). PHYSIOLOGYNEWS PN 3

As 2003 dawned, universities and their whole paraphernalia of courses in generic academics are themselves transformed financial problems at last featured promi­ skills, personal records of achievement, into balance-sheet managers. This danger nently on the government’s agenda, advisors, in-course assessment and so is arguably greater as departments get mainly due to the debate about how to forth. Research policy overall is driven by larger by successive mergers. Few depart­ fund increased student numbers. The the need for RAE rankings, as universities ments remain where the Head is respon­ option of top-up fees has provoked the constantly reorganise, amalgamate, and sible for 10 people whose work he or she most heated exchanges, particularly the abolish departments in order to maximise knows well. Faced with managing 40 or suggestion that an elite group of universi­ RAE scores. This is not to criticise the RAE more staff, many of whom are little ties – roughly speaking, the so-called panels, who do a thankless job with profes­ known to them, the easy solution for a Russell Group – would use a free market sionalism and integrity. The problem is the Head is to reach for the spreadsheets and in fees to break away and form a kind of use that universities make of the ratings. the tick-list. Alternatively, many universi­ ‘Premier League’. ties have instituted formal appraisal Of course, not all the developments have systems – more bureaucracy. By the time this issue appears we should been bad. Graduate students do need know the government’s plan for UK generic skills, and practice at presenting All this bureaucratic oversight and re­ higher education. But the fact that the data, and there should be some check on organisational drive clearly looks good to statement is awaited with such anticipa­ their progress. New ways of teaching, such someone – the Department of Education? tion – and trepidation – serves to illus­ as problem-based learning, have been The government? But does it actually trate, yet again, that universities in the UK brought in, particularly in medical courses. improve university teaching and research, primarily have one customer, the govern­ And we should periodically re-assess what or scholarship? After all, it is quality ment. Students are also customers up to the best way is to organise a department. teaching and research that is the true a certain point – witness the redundan­ But how many of the changes of the last mission of universities, not good scores in cies in several university departments of two decades do we really believe were league tables. This is true even if the engineering now that 6th formers academically driven, or justified? league table is one that explicitly grades research output, like the RAE. In any large increasingly reject engineering and other And there is a more systemic danger than organisation it is very tempting to substi­ ‘hard science’ degrees – but the primary simply dancing to the government’s tune. tute an external verdict for one’s own force shaping the future of the UK univer­ This is the creeping takeover of manageri­ judgement, as the UK’s burgeoning sities remains government policy. alism in the upper echelons of British consultancy industry demonstrates. But universities. If the main point of the As a result of this, the last 20 years have who is best qualified to assess how well a system is to maximize financial turnover, seen UK universities change hugely at the university department is doing? Its and to score well in government league behest of successive government initia- members? Its Head? Or an external panel tables, then the people in charge of the tives and the ever-increasing accompa- judging a paper submission? nying burden of audit and rankings. system will inevitably become managers Student numbers have expanded hugely, whose prime job is to ensure that these Whatever our view, we can probably all with no real increase in funding. Class ‘outcomes’ are delivered. agree that the answer is not ‘a university administrator’. sizes have risen, whether in lectures or At one level, this is manifested in increased tutorials, as student-staff ratios have control of universities’ academic priorities So senior academic staff in universities, doubled. The way we teach has also been by non-academic, or at best ex-academic, including scientists, face a major reshaped by the demands of exercises like administrators. This has become far more challenge as 2003 starts. If – hopefully TQA, which have imposed a huge burden common, since management by statistics when – the government delivers of bureaucracy on the system. As a conse- and balance sheet obviates the need for increased funding to the universities, quence, the issue of what is academically academic judgement. Take, for instance, they have to try and make sure that best in university teaching has to fight a department that scores unexpectedly extra money that reaches the system is with the demands of the balance sheet – poorly in the RAE. Any manager can see spent to improve teaching and research, how can we teach the most students for that this demonstrates clear underperfor- not targeted a priori on measures to YSIOLOGthe least money with the least number of mance, with the YNEWS solution typically being improve balance sheets, performance discipline-specific specialist staff? to remove the department from the next statistics and league table placings. RAE by dismantling it or merging it. This They have to behave like academics, A similar picture pertains in research. reasoningspring requires precisely2003 no academic numbernot administrators, 50 and fight their corner Turnover – in the shape of grant funding, | judgement in-house, since the academic for academic priorities. easily countable in thousands of pounds verdict has already been delivered by the per year per academic – is king. Bureau- Good luck to them. They will need it. RAE panel. cracy has flowered, with universities Austin Elliott creating Graduate Programmes and There is also the more insidious danger Graduate Schools, often virtual, with a that Heads of department and other senior 4 PN NEWCASTLE MEETING

Welcome to the University of Newcastle

Barry Argent Physiology is alive and well in decided to leave the University during Newcastle! Many of you will have the restructuring while Jim Reed has heard that a major restructuring of the been forced to retire through ill health. University of Newcastle upon Tyne has Their contributions are sorely missed. taken place over the past couple of Of course, there was a tinge of sadness years. On ‘big bang’ day, 1 August that such a successful unit as the 2002, the number of faculties was Department of Physiological Sciences, reduced from seven to three by a which had scored 5A in both of the last process of amalgamation and more RAEs and 24/24 in the QAA for its than 70 Departments became 28 Degree Programme, should have been Schools. The purpose of these changes disbanded. However, when the basket is to increase the efficiency of the gets shaken up it is inevitable that University’s operations and to create some of the golden eggs will get some financial headroom so that we broken. We take comfort from the fact can invest for the future. The restruc­ that the aim of the restructuring turing is core to our declared aim of process is to make the whole University making Newcastle one of the top 10 work as well as the Department of research universities in the UK. Physiological Sciences did in the past! As part of the restructuring, the three Looking to the future the School of Biomedical Science departments, Cell & Molecular Biosciences, which is including Physiological Sciences, were made up of units graded 5 and 5* in amalgamated into a new School of Cell the 2001 RAE, is one of the strongest & Molecular Biosciences, totalling close research groupings in the University to 50 academics. The Epithelial and has a political voice to match. The Research Group (Adrian Allen, Barry School has a post-genomic perspective Argent, Colin Brown, Dianne Ford, and much of the research activity is Below The University Quadrangle Mike Gray, Judith Hall, Barry Hirst, Jeff directed to the analysis of the function Bottom The University Arches Pearson, Nick Simmons, of gene products, i.e. functional David Thwaites, Andi genomics. The practical benefits of Werner) and the Cell being in a larger unit are already Signalling Research Group becoming apparent in terms of increases (Tim Cheek, Keith Jones, in the efficiency of teaching and admin­ Alex McDougall, Trevor istration. On the research front we look Jackson, Michael Whitaker), forward to a bright future with the whose laboratories have just opportunities for interaction and collab­ undergone a major refur­ orative research with our new colleagues bishment funded by a who have expertise in biochemistry, £750K grant from the Well­ genetics, molecular biology and micro­ come Trust, are both located biology being much enhanced. within this new School. This Newcastle meeting is a desig­ However, our Sensory nated meeting on Epithelia and Systems Group (Anya Hurl­ Membrane Transport. Newcastle has a bert, Gary Green, Adrian long history of excellence in epithelial Rees) have moved on to research. As well as the 11 academics pastures new in either the listed above there are three research School of Neurology, Neuro­ fellows, 13 post-doctoral workers and biology and Psychiatry or 21 postgraduate students in the Epithe­ the School of Biology. lial Research Group. Our aim is to Regrettably, David Sanders understand epithelial transport FEATURES PN 5

processes at the cellular and molecular and include level, and how their function and several major dysfunction relates to the whole awards in excess organism in vivo. Over the past 10 years of £300k from the we have assembled a group of active research councils. researchers who can deploy a variety of The centre­ methodologies ranging from genomics pieces of the April and proteomics, sophisticated electro­ meeting will be physiological techniques through to two symposia, whole animal physiology, including which reflect the transgenic mouse models. Our strategy interests of the for future development is to capitalise Newcastle Epithe­ on our collaborative strengths, our lial Research shared expertise, and our unique Group. Transport Entrance to the Medical School concentration of techniques (from & Signalling: From Gut to Brain and Back molecular through cellular and tissue Again (organised by David Thwaites to whole organism) to provide added and Andi Werner) covers signalling in value to our research. We address the gut, the transport of nucleosides, important physiological and patho­ drugs and amino acids, and neurotrans­ physiological problems related to mitter transport into synaptic vesicles. epithelia, with particular focus in the Epithelial Electrolyte Transport: Multi- following areas: Tasking & Hidden Talents (organised by i) understanding the molecular and David Thwaites and Mike Gray) covers cellular mechanisms underlying co­ ion channels, bicarbonate transport by ordinated responses of the intestinal SLC26 family transporters and its rela­ epithelium to changes in diet, with an tionship to cystic fibrosis, and the emphasis on transporter genes latest on the regulation of NHE3 by involved in protein-nitrogen assimila­ NHERF and the role of NHE3 in tion and in zinc homeostasis; congenital diarrhoea. The organisers ii) understanding the molecular and have assembled an impressive panel of cellular regulation of chloride channels international speakers and these in pancreatic and renal function and symposia promise to be memorable their dysfunction in cystic fibrosis and occasions. renal disease; In addition, we are privileged to host iii) how individual gene products are a number of the Society’s Lectures integrated to produce functional mucus during the meeting including the A.A. secretions; Harper Lecture (Michael Schemann, iv) how an inventory of drug trans­ Freising-Weihenstephan, Germany), porters already identified at the molec­ the Biller Prize Lecture (Louise Robson, Epithelial Research Group and guest speakers at our 2002 conference. Newcastle symposia organisers are ular level act to optimise drug delivery, Sheffield, UK), the GI Tract Designated in the back row: Andi Werner (fourth from left), Mike disposition and excretion. Gray (10th from left) and David Thwaites (11th from left) We have an active seminar programme (partly funded by the Society) and hold an annual two-day research conference. Our research funding comes from the MRC, BBSRC and the major research charities, and there are longstanding industrial links in areas such as mucus secretions and their interactions (Reckitt Benckhiser), and intestinal and renal drug transport (AstraZeneca, Glaxo-Wellcome/SmithKline Beecham). Current active grants total almost £2m 6 PN NEWCASTLE MEETING

Lecture (Gary Shull, Cincinnati, USA), in Newcastle also intend to maintain the Epithelia & Membrane Transport their contribution to the wider promo­ Designated Lecture (Shmuel Muallem, tion of physiology, in particular by Dallas, USA), and the Renal Physiology active participation in the varied func­ Designated Lecture (Edward Weinman, tions of the Physiological Society. Baltimore, USA). A meeting not to be Currently, David Thwaites is the missed if you are interested in Epithelia convenor of the GI Special Interest and Membrane Transport! Group, while Mike Gray is on the Edito­ Now that the Department of Physio­ rial Board of Experimental Physiology. logical Sciences has gone, the main As well as the organisational restruc­ focus for the discipline of physiology in turing of the University, those of you Newcastle has become our Physiological who have not visited Newcastle Sciences Degree Programme. Despite our recently will notice that a physical dispersal to different Schools we remain restructuring has also been taking place committed to the provision of high in both the University and the City. quality teaching in physiology (QAA The architecturally uninspiring 24), medicine (QAA 24) and dentistry entrance to the Medical School has (QAA 23). We also contribute to other been converted into a space age struc­ degree programmes within the School of ture by construction of a new 400 seat Cell & Molecular Biosciences (all QAA lecture theatre and a new research 24), including our new Biomedical building, the Henry Wellcome Sciences Degree. Recruitment into the Building, which houses our psycholo­ popular Physiological Sciences Degree gists. The City itself has also changed Programme is being maintained and the following massive investment by both growing reputation of Newcastle Top Barry Argent, Peter Hegyi (fellow) and Bernard University means that the quality of our Verdon (post-doc) entrants is improving. Currently we Centre Barry Hirst, Georgina Carr (PhD student) and have a final year of 45 students, made up Maxine Geggie (technician) of 40 physiologists and five intercalating Above Amy Windass (PhD student) and Colin Brown medical students. Perhaps the major benefit to arise so far from the merger of the old Biomedical Sciences Depart­ ments is improved efficiency of our teaching. Indeed, teaching in the first half of all our three-year degree

Below Andi Werner, Keziah Preston-Fayers (PhD programmes, to the 200 plus students student) and Chris Graham (post-doc) within the School, is now common. Bottom Ralph Bridgett and Bill Saint who run the While this has inevitably resulted in a School workshop reduction in the physiology content for students studying the subject at single honours, this is compensated for by their wider exposure to the molecular biology and immunology that under­ pins modern physiology. Moreover, this restructured teaching has had the added benefit of increasing the exposure of students on other degree programmes, such as biochemistry, genetics, microbi­ ology and immunology, to more advanced physiology teaching. For the

last 18 months of their study, the Top Medical student lecture in the new, 400 seat, students divide up into the smaller David Shaw lecture theatre degree specific groupings. Physiologists Above A medical physiology practical FEATURES PN 7

Memories of Leeds…

Right The Worsley Building

Far right Stewart Sage, Chair of the Editorial Board of The Journal of Physiology

Below Melanie Rees, Meetings Secretary’s Assistant and Chris Fry, Chairman of the Executive Committee and, below right, Mark Dunne, Meetings Secretary, acknowledge the Society’s appreciation as they come to the end of their terms of office

Above The Sage Gateshead Music Centre (currently under construction) with the Tyne Bridge in the background

Below Angel of the North

Newcastle and Gateshead Councils. The most spectacular results of this investment are the Gateshead Millen­ Right Ann Silver (left) and Melanie Rees nium Bridge, the Sage Gateshead (a Below Staff from the Department of Physiology in magnificent music centre) and the Leeds whose efforts helped to ensure a Baltic (a modern art gallery) where we successful meeting shall have the meeting dinner. And, of Bottom left John Sulston (left) and Colin Blakemore course, Antony Gormley’s masterpiece, Bottom right Melanie Rees, Bill Winlow and new Meetings Secretary Bridget Lumb Angel of the North, stands sentinel on our southern approaches. Newcastle has always been famous for its nightlife (as some of you will know from previous Society Meetings!), but we are now becoming a major cultural centre as well. These recent developments and much more underpin the Newcastle- Gateshead bid to become the European Capital of Culture in 2008. But fear not, in the midst of this cultural onslaught we have not forgotten our roots and we still boast about our excel­ lent beer and our above average foot­ ball team! Geordies the world over have a reputation for hospitality and we extend a warm welcome to the Physiological Society.

Barry Argent School of Cell and Molecular Biosciences University of Newcastle upon Tyne 8 PN TENERIFE MEETING

Recollections from Tenerife 2003: a truly first joint meeting

In 1996 a representative group of three discussion forums. In addition, British physiologists travelled to Sala­ two satellite courses for pregraduate manca to actively participate in the and graduate students, and a satellite XXVII Annual Congress of the Spanish debate also took place. A total of 305 Society of Physiological Sciences abstracts were accepted. Some of them (SECF). Two years later, a substantial were presented in previously desig­ delegation of Spanish physiologists nated symposia, and the rest were held their XXIX Congress in Liverpool presented either as oral communica­ coinciding with a British meeting. The tions or posters. Their distribution into agreeable and stimulating experience different subjects is shown in the Table. on both these occasions gave rise to the Further information can be obtained at Rafael Alonso, Congress Chairman idea of organising a truly joint meeting. http://www.seccff.org/congresoXXXII/index.php. To meet the British requirement of a ‘sunny place’, Tenerife was chosen and Fifty years of Spanish the University of La Laguna designated physiology: Negrin’s legacy the role of the host institution. Finally, When our British colleagues read Juan the first joint meeting between the Negrín’s name in the preliminary British and the Spanish societies took programme, they asked me about who place in Puerto de la Cruz from he was. As not even many young February 13 to 17. On behalf of the Spanish physiologists know Negrín’s Local Organising Committee, I would contribution to the development of like to thank the active participation of Spanish science, a brief introduction all attendants and to express my grati­ would be worthwhile. Juan Negrín tude to those British friends who (1892-1956) is best known as the Prime contributed with us in the organisation Minister of the Spanish Government of the scientific programme. As it has during the Civil War (1936-1939). A view of the north coast of been a successful and enjoyable experi­ However, he must be recognised as one Tenerife and the Teide volcano ence for every­ of the founders of modern Spanish body, I believe science (Tunón ~ de Lara et al, 1996). that it is time to When he was 14 years old, Negrín start organising moved to Germany and started his the next one. medical education in the University of About 400 Leipzig, in the Physiologisches Institut participants, founded by Carl Ludwig in 1865. including 67 During this period Negrín worked invited speakers, under the instruction of Theodor von with roughly the Brücke on the interactions between the same number endocrine and the nervous system, and from each society the regulation of the vascular tone. In attended the 1916, after gaining his doctoral degree, meeting. It Negrín planned to join Walter included seven Cannon’s laboratory at Harvard Univer­ mini-symposia on sity. However, he was forced to return a balanced selec­ to Spain to lead the Laboratory of tion of subjects, General Physiology that had been five plenary created in Madrid as the brainchild of lectures, three Santiago Ramón y Cajal. Only a few meet-the-expert years later he became Professor of Phys­ sessions, and iology at the University of Madrid. He FEATURES PN 9

then led an important project aimed to number of the development of experimental phys­ Spanish physiolo­ iology and the creation of a number of gists mainly active research groups in Spain. belong to the Negrín’s involvement in the organi­ fields of sational and financial problems of endocrinology science in Spain at that time stimulated and neuroscience, him to become involved in social with an impor­ issues. In 1934 he gave up his academic tant focus on the activities and totally dedicated his time cellular and mole­ to politics. The outbreak of the Spanish cular approaches. Civil War in 1936 and his exile in 1939 These trends are marked the tragic endpoint of this story. particularly To commemorate the 50th anniver­ important in sary of its first meeting, in conjunction several Spanish with the Juan Negrín Foundation, regions, where the SECF has created the Juan Negrín interdisciplinary Prize to honour an outstanding career research institutes in physiology. On this first occasion it have recently has been a pleasure to award it to been, or are in Erwin Neher. the process of being, developed. Physiology in Spain The SECF was created in 1952 and had Physiology at La Laguna its first annual meeting a year later in Host Departments and Madrid. Since then, it has not only teaching tasks been the source of all home-grown The host group that organised this generations of Spanish physiologists, meeting belongs to the Departments of but also the origin of several scientific Animal Biology and Physiology, societies on a broad scope of fields, together being comprised of about 25 such as biochemistry, cellular and permanent academic staff. Both are molecular biology, endocrinology, situated in the Faculty of Biological neuroscience, and pharmacology. This Sciences and the Medical School, scientific divergence has probably had respectively. Even though the buildings an undesirable atomising effect. Thus, are not so old and there is enough Top Lago Martianez at Puerto de la Cruz while some of these disciplines have space for laboratories, the structure has Above A typical old corner of Puerto de la Cruz developed with the impulse of new and deteriorated considerably and the need fashionable experimental technology, for modern facilities is now extremely the other on Basic Biomedical Research, physiology has somehow remained urgent. Because of this, several and another part also participate in a within the academic boundaries of members of these Departments, Neuroscience programme. teaching. In the last few years, however, together with others from the Depart­ the idea of reinforcing the core role of ments of Anatomy, Biochemistry and Research activities physiology to understand the under­ Molecular Biology, Cell Biology, and Physiology in Tenerife could be consid­ lying principles of the functioning of Medicine are working in the creation of ered as a relatively young research field, living beings – the logic of life (Boyd & a new research institute targeted to since it started in both the Faculty of Noble, 1993) – is clearly emerging. basic and applied biomedical sciences. Biological Sciences and the Medical Nevertheless, Spanish physiologists The two host Departments teach School in the mid 70s. However, after –either engaged with the SECF or with physiology to medical (current intake three decades of active research several any of its derived societies— have 125), nursery (75), physiotherapy (70), physiology teams are currently rated as extended into a wide number of depart­ pharmacy (200), and biology (150) being in the highest positions in the ments. Most of them work in universi­ students. Most members of the staff are University of La Laguna. The main ties and in research institutes, and very also engaged in two doctoral research lines in the host Departments few really do work in industry. A large programmes, one on Life Sciences and are related to neuroscience, marine 10 PN TENERIFE MEETING

Ion channels, membrane lipids and cellular responses to apoptotic agents Mario Díaz runs a group currently working on the mechanisms by which oestrogen and antioestrogen compounds modulate several types of ion channels in excitable cells. By using electrophysiological, biochemical and imaging techniques they are studying how oestrogens modulate contractile activity of mouse intestinal smooth muscle. These effects are apparently due to direct interactions of steroid molecules with L-type calcium and

BK(Ca) channels. In addition, Mario Díaz together with Covadonga Rodríguez, Tomás Gómez and Eduardo Almansa are studying the role of membrane lipid composition on the function of several intrinsic membrane proteins, including ion channels and membrane transporters. They are also The local organising committee. From left to right: Mario Díaz, Raquel Marín, working together with a group led by Guadalberto Hernández, and Rafael Alonso with the female rat gonadal axis at Antonio Lorenzo on the identification both hypothalamic and pituitary levels. of the physiological basis for the essen­ science, and reproductive neuroen­ Manuel Mas is extending classical tiality of certain fatty acids on fish docrinology. In addition, members studies of erectile responses in rats with growth and development. engaged in active research are inte­ spinal lesions with the dynamics of grated into more interdisciplinary nitric oxide release at central and Temporal dynamics encoding infor­ groups with people from other Depart­ peripheral levels. In addition, together mation in the nervous system ments and clinicians working on with andrologists, he is evaluating the Julián González, Luis de Vera, and different aspects of developmental, evolution of sexual function in human Ernesto Pereda are using linear and metabolic or neurological diseases. subjects with spinal lesions and the non-linear technical approaches to Presently, the different research teams response to erectogenic agents. Carmen analyse temporal series from brain and can be grouped into the following areas: González is working on neuroimmu­ heart electrical activity, both in noendocrine interactions and the role humans and experimental animals. A Neuroendocrinology and oestrogen­ of local agents in the regulation of pitu­ particular area of interest is the analysis mediated neuroprotection itary secretions. A particular area of of the non-linear relationships between Reproductive physiology has been a recent interest is the characterisation of cardiorespiratory and brain activities permanent research area in La Laguna. novel mechanisms involved in during awake and sleep stages, as well While whole animal studies were the oestrogen signalling both in endocrine as during some noxious situations such current model to investigate the repro­ and neuronal cells. An integrated team as sudden death in the newborn. ductive system in the past, more composed of Rafael Alonso, Mario Díaz, Furthermore, by using these mathemat­ cellular and molecular approaches are Raquel Marín, Borja Guerra, and Araceli ical approaches, they are also character­ now being used to characterise the Morales is using neuronal cell lines to ising the interdependencies and interactions between peripheral analyse the interactions between intrinsic variability on brain-derived hormones and central neurons. Thus, oestrogen hormones and their poten­ electrical signals while performing Rafael Alonso, Guadalberto Hernández, tial neuronal targets. One of the main specific perceptive tasks. By using and Pedro Abreu, in collaboration with aims of this research line is the identifi­ similar methodological and conceptual the industry, are characterising the cation of neuroprotective effects of approaches, Juan V. Sánchez-Andrés is mechanisms and signalling pathways oestrogens and the characterisation of analysing the temporal signals which by which oestrogens and selective the specific receptors and the under­ encode relevant information in oestrogen receptor modulators interact lying action mechanisms. excitable cells, such as the pancreatic FEATURES PN 11

beta cell and the pyramidal neurons of electrophysiological, CATEGORIES ORAL POSTER TOTAL the hippocampus. The general hypoth­ behavioural, and morpho­ esis underlying this research line is that logical methods. In addi­ Autonomic function 3 3 the characterisation of the signalling tion, in collaboration mechanisms participating in synchro­ with a team of neurolo- Blood-brain barrier 3 3 nous cellular activity may help to gists they are working on Cardiovascular & respiratory control 10 12 22 understand the pathophysiology of the design of different Cell signalling 10 17 27 some diseases involving alterations in pharmacological and the pattern of excitability. surgical strategies in the Cellular neurophysiology 18 16 34 prevention and treatment Comparative physiology 17 17 Neuronal vulnerability and neuro­ of Parkinson’s disease. Development & plasticity 4 4 protection Manuel Rodríguez and Tomás González Neurochemical Epithelial & membrane transport 10 23 33 (from the Anatomy Department) are monitoring and Gastrointestinal tract 13 13 trying to characterise the mechanisms neuroimaging Heart & cardiac muscle 6 6 underlying neuronal degeneration of José L. González-Mora the dopaminergic system in Parkinson’s works in an interdiscipli- Integrative neurophysiology 9 9 disease. During the last few years they nary group mainly Ion channels 7 14 21 have developed some useful animal involved in the develop­ Microvascular & endothelial physiology 8 2 10 models of Parkinson’s disease which ment of new techniques allow them to carry out direct testing aimed at real-time Muscle contraction 8 6 14 of the working hypothesis. Thus, the monitoring of neuroac­ Neuroendocrinology 8 14 22 role of intrinsic and extrinsic factors tive molecules in Renal & respiratory physiology 9 9 affecting dopaminergic synapses are experimental animals. being analysed by a combination of In addition, in collabora- Reproductive physiology 7 7

tion with other Depart­ Sensorimotor physiology 10 7 17 ments of the University Smooth muscle 10 13 23 of La Laguna and members of the Institute Teaching 7 7 of Astrophysics, they are developing some TOTAL 99 202 301 devices to ameliorate Table Subject distribution of oral communications and posters sensorial deficiencies in people suffering from neurological diseases. In this respect, general framework of the ITB will be a virtual acoustic space has recently that of biodegeneration, with a partic­ been designed to allow perception in ular emphasis on their neural aspects. blind people. We are confident that next time we As mentioned above, the need for organise a meeting it will be hosted in interdisciplinary approaches has the new facilities of the ITB. induced us to work towards a highly integrated research project. About 30 Rafael Alonso staff members and an equivalent Chairman of the Joint Meeting at Tenerife number of fellows are now in the Chairman Elect of The Spanish Society of Physiological Sciences process of establishing the Institute of [email protected] Biomedical Technologies of Tenerife (ITB). By incorporating people from a broad scope of disciplines, we are developing a strategic plan aimed at References

Top Mario Díaz at the confocal imaging system the search for technological solutions Boyd CAR, Noble D (1993) The Logic of Life. Oxford University Press, Oxford. Centre Guadalberto Hernández trying to get blood to those biomedical problems derived Juan Negrín López (1996). El hombre necesario. Tuñón from the hypophyseal portal vessels of the rat from the interaction between ageing de Lara M, Miralles R, Díaz-Chico BN (eds.). Ciencia y Bottom Raquel Marín in the culture room and environmental injuries. Thus, the Tecnología en Canarias, Santa Cruz de Tenerife. 12 PN FEATURES

Limbs in limbo: the problem of targeting Keri Lee Page focuses on the problems inherent in an action as apparently simple as scratching an itch

If you had some food on your cheek, by a stereotyped three-step motor you’d probably wipe it away and if you sequence involving both the head and had an itch you’d most likely scratch it. the forelegs (O’Shea, 1970). Targeting We do these things instinctively, can also play a role in other contexts: without a second thought. But in stick insects, for example walking directing the trajectory of a moving and climbing use targeting. The middle limb so that it meets up with a target in and hind legs are targeted to step down Keri Lee Page space is a complex computational task. directly behind the tarsus of the ante­ For targeting to be successful, a human rior leg, no matter how the position of or animal must translate a set of spatial this limb is perturbed (Cruse, 1979). co-ordinates – the target position, encoded by exteroceptive sensory inputs – into a co-ordinated temporal activation of motor neurones, which is ultimately responsible for the final movement. There is also the problem of kinematic redundancy. This is when the same target can be reached by an Figure 1 A Photograph of Schistocerca gregaria with trajectory for a posterior scratch superimposed. infinite number of different motor B Stick diagram of leg movements during a scratch patterns, requiring that targeting directed towards an anterior stimulus site. networks must have some criteria for C Stick diagram for a posterior stimulus site ‘selecting’ the most appropriate motor action. Nevertheless most animals, Figure 2 Wing hair distributions for male (A) and female (B) wings. Coloured dots correspond to three from cockroaches to cats and hair length categories. Wings were divided into 9 bins cephalopod molluscs, can do it all as that split the surface area into 5 anterior to posterior well as we can (Figure 1) segments and into dorsal and ventral halves. The wing tip was treated as a single bin. Numbers are the Much of what we currently know mean probability of a scratch being elicited by stimuli about vertebrate limb targeting comes in the corresponding bin from studies of episodic reaching in primates and rhythmic scratching in Targeted scratching in locusts cats. In the early 1900s Sherrington My research in Dr T Matheson’s lab in demonstrated that chemical or tactile the University of Cambridge Zoology stimulation of the body surface in cats Department focuses on targeted and dogs can elicit rhythmic directed scratching in locusts as a model system, scratching movements of a hindleg. and addresses the problems inherent in Many animals have scratch reflexes an action as apparently simple as that have several forms, depending on scratching an itch on a wing (Math­ the location of the stimulus site. This is eson, 1997). well known in the frog and turtle but is Tactile stimulation along the length not the case with cats. In turtles three of the wings elicits different targeting distinct reflexes exist (rostral, caudal and movements of the hindleg that scratch pocket scratches) with blends of each the stimulus site (Figure 1). For this occurring at stimulus transition sites. targeting to be successful, the stimulus Invertebrates do remarkably well at position first has to be encoded. This is the same tasks. Locusts clean their usually done by way of a somatotopic antennae with an antennal cleaning map of afferent neurones from the groove on the tarsus. This groove is mechanosensory hairs on the body brought into contact with an antenna surface. These arborisations synapse FEATURES PN 13

The larger number of hairs in females ascending, intersegmental interneu­ correlates with an overall increased rones have been proposed as candidate probability of scratching for a given neurones for the convergence of spatial stimulus. Despite the larger number of information from the wing and posi­ mechanoreceptors on female wings, tional information from the chordo­ the females do not target with greater tonal organ of the hind leg. Interneu­ accuracy than males (Figure 3). This rones with bilateral arborisations may may indicate that increased sensory be responsible for the distribution of input causes greater levels of excitation spatial information that enables simul­ in the central networks of females but taneous targeting of the contralateral that receptive fields are no more finely leg. Limbs in other body segments may tuned by the presence of additional also receive information from hairs. In other words, the hairs may ascending interneurones, enabling synapse onto the same number of interganglionic co-ordination (Math­ interneurones in both sexes. eson, 2002). This produces reflexes in The position of a limb is known by a the middle and forelegs which ‘position sense’ arising mainly from contribute to increased body stability proprioceptors within the joints. In while the hind leg is busy scratching. locust scratching, hind leg position is Interneurones involved in collation primarily described by feedback from must be integral to the network respon­ the femoral chordotonal organ. This sible for computing the final motor receptor spans the femur-tibia joint pattern. Non-spiking interneurones in and monitors the static position of the the metathoraic ganglion which are limb as well as direction, velocity and known to control sets of leg motor acceleration of any tibial movement neurones, are likely to be responsible (Figure 4). for much of the interjoint coordination As the tibia is moved, the cuticular that is characteristic of a scratch.

Figure 3 A Scratch probability in males versus apodeme (tendon) stretches the body females. B,C Accuracy in terms of closest distance of the chordotonal organ accordingly, Are central pattern to target in both males and females for an anterior resulting in stimulation of the recep­ generators involved in stimulus site (B) and a posterior stimulus site (C) tors. The receptors project into the targeted scratching? onto interneurones at the second level central nervous system where their In locusts, scratches are incredibly vari­ of the map in such a way that each patterns of branching correlate with able. This suggests two possible interneurone represents a distinct area of each response type. Identified local and scenarios: firstly there may be many the body surface called a receptive field. Maps have been described for the Figure 4 Light micrograph of the locust hindleg femoral chordotonal organ showing the somata of the approximately 55 largest neurones that respond to movements of the femur-tibia joint mechanoreceptors on locust legs, but have not yet been described for the wing surface. As a first step, a count and distribution analysis of the wing hairs has been conducted. This reveals a characteristic spread of hairs along the main veins of the forewing. Where hairs are more densely distributed, the likelihood of eliciting a scratch with tactile stimulation is increased, resulting in probability differentials across the wing surface (Figure 2). Surprisingly, there is a significant difference in the number of hairs between males and females – over and above that which would be expected due to the females’ larger body size. 14 PN FEATURES

distinct receptive fields that elicit ered at present: is a rhythmic CPG in discrete motor patterns which differ the traditional sense actually present at along the anterior to posterior axis. all? An alternative is that a population­ Alternatively, there may be a single coding scheme amongst interneuones motor pattern that is modulated in a may produce both linear targeting and continuously variable way by under some conditions, cyclical somatosensory feedback from the repeated movements. Such a notion wing hairs. Recent work in the lab might describe the generation of cyclic Figure 6 Tarry 1 and 2. Developed and built by the Department of Engineering Mechanics at the University suggests that the latter explanation is targeting movements without relying of Duisburg and tested with WalkNet at the Department correct. Descriptions of the circuitry on the standard concept of an of Cybernetics at the University of Bielefeld. Each that might underlie these alternatives, autonomous oscillating unit. model is approximately 40cm in length and the evidence that supports them In order for targeting to remain accu­ proven successful by its implementa­ is convoluted. rate, the networks must behave plasti­ tion in Tarry, a six-legged robotic insect The existence of central pattern cally with regard to external perturba­ (Figure 6) Biomimetic robots like these generators (CPGs) is supported heavily tions. For example, if a load is added to not only have consequences for the by studies of vertebrate targeting. The the hindleg of a scratching locust, feed­ future of autonomous robots but also scratch reflex can be elicited in the back from the campaniform sensilla for the study of targeting, as the robots decerebrate cat and spinal turtle and femoral chordotonal organ allows themselves throw up new lines of (Robertson et al 1985). Some studies on compensation for the extra weight, so enquiry in the real animals studied by locust scratching indicate discrete that accuracy is not reduced. In frogs neuroscientists. motor patterns for different stimulus too, loading does not affect the animal’s sites. This too suggests the existence of ability to remove the stimulus. It will a set of distinct CPGs, being activated be interesting to see from our future by specific inputs. These distinct experiments with locusts, how manipu­ patterns remain in a de-efferented and lating the proprioceptive signals from decerebrate animal (Berkowitz et al the chordotonal organ will affect 1996). My work, however, indicates targeting accuracy and whether the that interfering with proprioceptive system is plastic enough to recalibrate feedback has a significant effect on the the proprioceptive feedback over time, motor pattern’s efficacy (Figure 5). bringing the accuracy back into line. Such findings would imply that feed­ … if you had an itch you’d most likely scratch it back is used to fine-tune the outputs Future implications of from CPGs. Moreover, other work in targeting studies Keri Lee Page the lab suggests that for sites on a wing, Targeting studies have wide ranging Department of Zoology University of Cambridge a single CPG output exists, that is implications for technology and future strongly modulated by somatotopic research. The principal focus of verte­ REFERENCES input encoding the stimulus site. An brate studies is to consider mapping in BERKOWITZ A & LAURENT G (1996). Central alternative view of motor pattern the spinal cord and also the role the generation of grooming motor patterns and interlimb generation is therefore being consid- motor cortex plays in the processes coordination in locusts. J Neurosci. 16, 8079-8091. linking sensation and action. Mathe­ CRUSE H (1979). The control of the anterior extreme position of the hindleg of a walking insect, Carausius matical models of these processes may morosus. Physiol Entomol 4, 121-124.. eventually give rise to developments in CRUSE H, KINDERMANN T, SCHUMM M, DEAN J & robotic prosthetic-limb design. Inverte­ SCHMITZ, J (1998). Walknet – a biologically inspired network to control six-legged walking. Neural Netw brate studies too, have important 11, 1435-1447. implications for robotics, since the MATHESON T (1997). Hindleg targeting during invertebrate targeting paradigm should scratching in the locust. J Exp Biol 200, 93-100. prove easier to model. Modelling of MATHESON T (2002). Metathoracic neurones integrating intersegmental information in the locust. neural networks involved in the J Comp neurol 114, 95-114. targeted stepping movements of stick O’SHEA MR (1970). The antennal cleaning reflex in insects has led to the development of the desert locust schistocerca gregaria (Forsk.). In Proc Int Study Conf Current & Future Problems of WalkNet – an artificial neural network Figure 5 Ablating the chordotonal organ apodeme Acridology. London. Pp 55-59. removes proprioceptive feedback and reduces that controls six-legged walking (Cruse ROBERTSON GA, MORTIN LI, KEIFER J & STEIN PSG targeting accuracy et al1998). WalkNet has since been (1985). J Neurophysiol 53, 1517-1534. FEATURES PN 15 pH phantoms – a physiological phenomenon? Recently Christof Schwiening’s lab has shown that fast local pH shifts can occur in nerve cells. But now he is perplexed. The shifts seem to be large, even during modest amounts of electrical activity. Why has no one seen them before? Are they just phantoms? If they are real, are they important or not?

pH and but to different degrees, it has long neuronal been supposed that pH must be under excitability extremely tight control. Were this not Only small to be the case then a metabolic mess changes in pH are would occur, with some reactions required to proceeding too fast and others too produce marked slowly. The result of this mess would be alterations in a decline in normal physiological func­ Christof Schwiening neuronal tion. This view of pH homeostasis is excitability. It has been known for over supported by the exquisite control our Figure 1 In most neurones pHi depends upon the 150 years that excessive carbon dioxide bodies place on blood pH through the activity of several plasma membrane transport mechanisms. Not all acid fluxes are shown here e.g. acts as a CNS depressant, whilst a lack modulation of breathing. Furthermore, - + HCO3 flux through GABA-activated channels, and H of carbon dioxide induces hyperex­ the fact that almost all cells maintain flux on the glutamate uptake transporter. citability (see references in Somjen & intracellular pH (pHi) about 1 pH unit Tombaugh, 1998). Indeed, you can test more alkaline than would be expected the effect yourself by first hyperventi­ from passive diffusion of H+ (or indeed + - 1 lating (which lowers carbon dioxide H3O or OH ) across the plasma levels in the blood) and then by membrane supports this idea of active rebreathing air expired into a paper bag pH regulation. Thus, the view now (which raises carbon dioxide levels). commonly held is that pH, at least of Over the past 50 years this link nerve cells, is stabilized at an optimum between CO2, pH (see Box 1) and level by pH regulating mechanisms neuronal excitability has been the (Figure 1). subject of much experimental work It was with the study of pH regula­ (Tombaugh & Somjen, 1998). Never­ tion that my interest in neuroscience theless, I think it is fair to say that most began. As a PhD student I impaled BOX 1 Carbonic basics neuroscientists regard pH as irrelevant locust neurones, generally unsuccess­ ↔ + - when considering synaptic mecha­ fully, with ion-sensitive microelec­ CO2 + H2O H + HCO3 nisms. Of course all experimental elec­ trodes in an attempt to discover the The reversible hydration of CO2 gives + trophysiologists take extreme care with mechanisms that regulated pH. At the rise to acid equivalents (H ) in a reaction catalysed by the zinc­ the pH of their patch and bathing solu­ time the idea generally held was that containing enzyme carbonic anhy­ tions – heaven forbid that they are the gradual leak of H+ into cells, down drase (CA). There are at least 14 its electrochemical gradient, and meta­ more than 0.1 pH unit out. Experimen­ different isoforms of CA in mammals. + + tally pH is clearly important, but physi­ bolic H production represented the H It is found in the cytoplasm, mito­ ologically relevant? Never! For example load that the regulating mechanisms chondria, attached to membranes take an up-to-date review on neuronal tirelessly fought. To investigate pH and in fluid secretions. CAII is synaptic plasticity (Zucker & Regehr, regulation it was deemed necessary to amongst the fastest enzyme known – 2002) and look for a mention of pH – perturb pH by the addition of exoge­ its operation is nearly as fast as diffu­ sion of H+ will allow. CA inhibitors there is none. How is it that pH has nous acid and study the ionic depen­ slow the reaction between H+ and come to be so ignored? dence of the subsequent pH recovery - HCO3 , and thereby magnify pH (Thomas, 1984). It was already known shifts. CA inhibitors are used to treat a Intracellular pH regulation that snail neurones and squid giant diverse set of disorders including; The downfall of pH lies partly in its axons regulate pH with a plasma­ glaucoma, mountain-sickness, + - - very importance. Since the rates of all membrane Na -dependent Cl /HCO3 migraine, epilepsy and even cancer. enzyme reactions are sensitive to pH, exchanger (Figure 1). To many in the 16 PN FEATURES

to look at calcium buffering in snail Of course those working on red Red blood cell neurones (a model nerve cell). I was blood cells had known for some time calcium pump failing to measure calcium levels with that their PMCA could transport Much of what we know about the calcium-sensitive microelectrodes protons – but this was considered by plasma membrane calcium pump whilst Helen Kennedy was having them an irrelevance in a system with (PMCA) comes from work on the red

BOX 2 problems persuading colleagues that little calcium permeability and oodles blood cell (RBC). For instance in snail neurones showed no sign of a of other H+ flux (see Box 2). It is a 1982, some 10 years before our work plasma-membrane Na+/Ca2+ exchanger. shame that for 10 years those working on snails, Niggli et al showed that the RBC PMCA counter-transports H+ At the time it was widely believed that on neuronal pH regulation were seem­ (although there was some dispute on neurones extruded the bulk of their ingly unaware of the RBC literature. this point; see Rossi & Schatzmann, calcium on the Na+/Ca2+ exchanger. Armed with a Wellcome Trust Career 1982). But this counter-transport of H+ Roger Thomas, on the other hand, was Development Fellowship I then set was of little physiological importance having plenty of luck measuring extra­ about looking at activity-dependent pH since the transmembrane calcium flux cellular surface pH shifts. I wondered if shifts in neurones. - is small and HCO3 movements on - - I could measure surface calcium the Cl /HCO3 exchanger dominate changes. By lowering extracellular BCECF v HPTS pH. Interestingly, those working on neuronal pH were unaware of this calcium to about 1/50th of its normal My initial experiments using a pH­ RBC work showing a link between level I was able to see calcium disap­ sensitive dye called BCECF failed all too calcium and pH. pearing from the external surface frequently. This fluorescein-based dye In 1993 Gatto and Milanick reported during depolarisation (presumably was hard to load into snail neurones that the fluorescein-based pH-sensi­ entering the cell through voltage-gated through the patch pipette. The pipettes tive dyes are potent inhibitors of the calcium channels) and then gradually frequently blocked and my signals were PMCA. Worryingly some scientists are re-emerging following repolarization. buried in the noise. At that point I still using such fluorescein-based Removing external Na+ did not prevent began to try out other pH-sensitive dyes, such as BCECF, to measure pH the reappearance of calcium, but the dyes. I found a cheap dye (£15 per in cells that rely on the PMCA to intracellular injection of vanadate (an gram, of which I still have some left) extrude calcium. inhibitor of ATP-dependent pumps) called HPTS which seemed to perform did. This seemed to implicate the excellently, although few others used department in Bristol my study on calcium pump in snail neurone calcium it. Presumably its lack of popularity was locusts was esoteric and rather dull. extrusion. Furthermore, after a month because it was not available in a Maybe they had a point. of frenetic experiments, I managed to membrane-permeant form. To my During my first post-doc, in the USA, show that the calcium extrusion was horror I also discovered, from the red I saw others trying to make the study of coupled to the inward transport of H+ blood cell literature, that BCECF was a pH both exciting and trendy. I was intro­ and that it was the calcium pump that potent inhibitor of the PMCA! (see Box duced to a phenomenon we called the gave rise to the extracellular alkaline 2) Most workers measuring pH in ‘ugly monster’, a pH change resulting shifts that Roger had been recording. neurones, at the time, seemed unaware from the activation of an extracellular We were very excited by this discovery of both the blocking effect of BCECF solute receptor. I was also set to work of the counter-transport of H+ on the on the PMCA and the link between the on the intense activation of acid extru­ plasma membrane calcium pump PMCA and pH. This was to some extent sion in hippocampal neurones, which I (PMCA; also known as the Ca2+-ATPase reasonable since, at the time, it was was told might underlie memory! Both, or calcium-hydrogen pump) since it assumed that most neurones had little unfortunately for me, turned out to be seemed to us that it might explain a PMCA activity. My experiments with artefacts. Finally, I got involved in an whole host of pH changes in the CNS. the non-blocking pyranine-based pH­ expression cloning project, but it came Nature was, however, not impressed – sensitive dye HPTS and a potent to nothing. I left after a year, wary of and who can blame them, after all this blocker of the PMCA, eosin, seemed to both artefacts and molecular biology. was work from snails – and the work show that the PMCA was the main As I travelled back across the Atlantic was published in an austere but august endogenous acid loader in snails. no doubt there was a collective sigh of journal (Schwiening, et al 1993). Now I When the PMCA was blocked the relief from the lab! believe it is reasonably well accepted calcium-dependent pH shifts that some of the pH shifts seen in the temporarily disappeared before reap­ Activity dependent pH vertebrate CNS do indeed arise from pearing possibly due to mitochondrial changes the counter-transport of H+ on the dumping of acid. In 1996, with another In 1992 I was being funded by the MRC PMCA (Trapp et al 1996). two years of my Fellowship to go, I FEATURES PN 17

obscure the weak dendritic and axonal for our mammalian neuronal prepara­ signals. At the time, neither of us had tion was fortuitous. They turned out to had any experience of confocal be ideal for confocal imagery and easy microscopy and we were given the to patch. The data analysis was, impression that there were many obsta­ however, more of a challenge and led cles ahead. Indeed, the signals we me to write a little bit of software (see obtained from the processes were small, my home page if you want a copy!) to

less than a hundredth of those that perform regional pixel-by-pixel F/F0 could be got from the soma. Further­ plots (see Box 3). Characterizing the

more, since the diffusion of the dye, pHi shifts was also not simple. The from the patch-pipette to the processes, Purkinje cells are architecturally was relatively slow we had to be careful complex and attempting to control Figure 2 A confocal reconstruction of a patch­ not to ‘bleach’ too much of the dye. But, membrane potential throughout the clamped Purkinje neurone (cell body diameter ~25µm), in a cerebellar slice, taken at the end of an experiment. since we could use quite a high concen­ dendritic ramifications with the patch tration of the dye, these turned out to pipette is almost certainly a lost cause. took up a lectureship in Cambridge. be relatively minor problems. One of

My first attempts to measure regional the great advantages of HPTS, over most BOX 3 pH in neurones were made using a of the fluorescein-based dyes, is that Fluorescence fluorescence imaging system and when excited with either the 488 nm measurement of pH freshly isolated rat hippocampal or 458 nm line of the Argon ion laser Determination of absolute pH with neurones. It was, frankly, a disaster the entire fluorescence is pH sensitive – fluorescent dyes requires ‘ratiometric’ measurements. Typically this involves from start to finish. Then after those there is no pH-insensitive ‘pedestal’ fluo­ the pixel-by-pixel division of dye fluo­ three frustrating years with few results rescence. This allows the single wave­ rescence excited by two different but many ideas, the MRC awarded us length fluorescence shifts to be calcu­ wavelengths. The two wavelengths with a de novo Co-Operative Group lated without the need for any laborious are chosen such that one produces a Grant. This included the funds to buy a calibrations.2 To our knowledge this was pH-sensitive fluorescence and the confocal microscope and investigate, the first time that HPTS had been used other a pH-insensitive fluorescence. In amongst other things, pH shifts in snail on a confocal to follow regional pH, and this way one can correct for dye neurones and rat cerebellar Purkinje it took quite a time before we felt confi­ concentration, illumination and fluo­ rescence collection variables as well as neurones (Figure 2). dent with the measurements we were path length. However, the lasers in making. Figure 3 shows such a calibrated conventional confocal microscopes Confocal microscopy in pH image of a snail neurone during a cannot emit the wavelengths neces­ Cambridge depolarisation to +40mV. The lamel­ sary (~400 nm) to produce a pH­ To make spatial recordings of pH we lipodia are clearly subjected to much insensitive signal from our favoured (Debbie Willoughby and I) planned to larger alkaline pH shifts than the cell pH-sensitive dye, HPTS. Hence we are image the pH-sensitive fluorescence of body. Although some had predicted forced to make single-wavelength HPTS (Willoughby et al 1998) on the that such pH gradients must exist in fluorescence measurements. Such single-wavelength measurements of confocal microscope. Because the neurones (eg Tombaugh, 1998), seeing pH-sensitive fluorescence cannot be confocal scans a beam of light across the them directly was very exciting. calibrated with accuracy. However, preparation, rather than illuminating it HPTS has an unusual property that all in one go, the very bright cell body Rat Purkinje neurones does allow relative fluorescence shifts fluorescence does not (necessarily) The choice of cerebellar Purkinje cells (F/F0) to be turned into calibrated pH shifts, even if the absolute pH can only be guessed2. This calibration of the

1 pH F/F0 signal works best when the dye is in a stable system – i.e. for measuring 0.5 pH relatively rapid pH transients. A new generation of blue diode lasers, 0 pH as used in DVD technology, should A B allow future confocal users to make absolute pH measurements without Figure 3 A Transmitted light image of a whole-cell patch clamped snail neurone. B The needing to resort to expensive UV­ transmitted light image superimposed on the pseudocolour HPTS confocal pH image taken during a 1s depolarisation to +40mV. Warmer colours indicate a rise in pH. The lamellipodial lasers or two-photon microscopes. alkalinization is due to H+ efflux through voltage-gated proton channels. 18 PN FEATURES

the uptake of calcium into internal magnify the size of activity-dependent stores (mitochondria or endoplasmic pH shifts. Amongst these disorders are reticulum). We do not know whether two that are known to involve muta­

pHi is uniform across the Purkinje cell tions of the P/Q-type calcium channels at ‘rest’. If the dendritic spines are the (hemiplegic migraine and episodic sites of H+ influx into the cytosol, it is ataxia type II; see review by Kullmann, possible that the pH shifts there might 2002). The clinical effectiveness of be much larger (and indeed faster). Then acetazolamide has been assumed to be

we come to the question: do these pH due to an effect on resting pHi. shifts really occur physiologically? After However, given that the disorders are all these are brain slices where the blood associated with impaired calcium Figure 4 Simultaneous regional calcium rise and supply has been removed, they are at influx during depolarization – and acidifications, following a single short (10 ms) room temperature, the cells are being therefore presumably smaller calcium­ depolarisation to 0 mV, in the regions indicated on the partial 3D reconstruction (1 primary dialyzed with a patch pipette solution dependent pHi shifts – it is more likely dendrite, 2 secondary dendrite, 3 tertiary and artificially stimulated. This is far that acetazolamide is simply restoring dendrite). Superfusate buffered with HEPES, from physiology. But imaging pH in the otherwise blunted pHi shifts (Figure patch solution containing CsCl, x40 objective nerve cells in a functioning brain 5). Such a hypothesis, of course, relies (Schwiening & Willoughby, unpublished). during physiological stimulation (eg on the assumption that pHi shifts play In the end blocking inhibitory input tickling a paw) takes more money than an important role in normal neuro­ with bicuculline and dialyzing with Cs+ the MRC can currently pay and more physiology and that their absence (to block K+ channels) turned out to be time than the University, driven by results in a profound dysfunction. This about the best we could do for voltage research assessment objectives, will is not what most neuroscientists clamp recordings. But, as you can see allow. But, we can dream! currently appear to think. from the prolonged dendritic calcium If we cannot perform the experi­ trace in Figure 4, this tended to result ment, can we at least muse on the Whither? in the dendritic regions ‘hanging up’ at possible roles of these pH shifts? There At this point it is not clear that we positive potentials for rather longer are a couple of pieces of evidence that know the full extent of these local pH than the cell body. Thus we also used might suggest that they are important signals since they have not yet been trains of back propagating action in normal physiology. Both sets of measured in locations where they are potentials (again with bicuculline experiments involve modifying pH likely to be largest; pre-synaptic termi­ present, but no Cs+). The results were buffering. Firstly, in experiments on nals and dendritic spines. Nevertheless, very similar in both cases. Electrical isolated hippocampal neurones, it has the investigation of the physiological activity, even in the presence of physio­ been shown that increasing the (and indeed clinical) importance of - logical amounts of CO2/HCO3 and concentration of intracellular pH buffer these pH shifts seems worth some effort. carbonic anhydrase activity, caused can modify neuronal calcium signals. dendritic pH shifts (~0.1 pH unit for (Tombaugh, 1998). The introduction of either 1 s depolarisation or a 10 s burst excess pH buffer into cells should not of action potentials) that were about directly alter pHi. It has been suggested three times larger than that seen in the that the pHi shifts that normally occur cell body. By combining a calcium­ during electrical activity (Trapp et al sensitive dye (Fura-red) with our pH­ 1996) might be blunted by the addi­ sensitive dye we began to look at tional buffer. However, in his study, whether these heterogeneous pH tran­ Tombaugh was unable to make record­ sients occur as a result of differences in ings of these dendritic pH shifts. The the calcium transients, or whether second set of experiments, or rather there might be other factors at work, observations, are from human clinical such as local pH regulation. studies. Figure 5 Calcium fluxes at dendritic spines could Of course, there are many questions result in physiologically important pH shifts (pH). remaining. Although we know that Cerebellar ataxia Carbonic anhydrase inhibition would be expected to these pH shifts are dependent upon Certain types of CNS disorders can be magnify these shifts (by reducing pH buffering, see calcium influx, we do not know what is treated with inhibitors of carbonic Box 1). In cases where impared calcium fluxes (eg episodic type II ataxia) result in smaller than normal causing them. We assume that it is the anhydrase (such as acetazolamide). pH shifts, carbonic anhydrase inhibition might be able PMCA, but it could equally result from Such inhibition is well known to to magnify the pH signals and restore normal function. FEATURES PN 19

However, we have few tools (eg References Nitric oxide microsensors blockers) with which to study these Gatto C & Milanick MA (1993). Inhibition of the functions. In order to remove the pH red blood cell calcium pump by eosin and other fluorescein analogues. Am J Physiol 264, C1577­ Roger Wadsworth reports signals it is currently necessary to 1586. on a symposium to discuss abolish the transmembrane calcium Kullmann, DM (2002). The neuronal fluxes – hardly a specific blocker! channelopathies. Brain 125, 1177-1195. the physiological Niggli V, Sigel E & Carafoli E (1982). The purified Manoeuvres designed to enhance the Ca2+ pump of human-erythrocyte membranes measurement of nitric pH shifts have little to add to our catalyzes an electroneutral Ca2+-H+ exchange in oxide using electrochemical knowledge since they might only reconstituted liposomal systems. J Biol Chem 257, 2350-2356. reveal what the physiological buffer microsensors held at the Rossi JPFC & Schatzmann HJ (1982). Is the red cell systems may normally attempt to calcium pump electrogenic? J Physiol 327, 1-15. European Society for prevent. Schwiening CJ, Kennedy HJ & Thomas RC (1993). Microcirculation 2002 To restrict our interest to neurones Calcium-hydrogen exchange by the plasma membrane Ca-ATPase of voltage-clamped snail would also be a mistake. There must meeting in Exeter neurons. Proc R Soc Lond 253, 285-289. be researchers working on non­ Schwiening CJ & Willoughby D (2002). neuronal cells for whom local pH Depolarization-induced pH microdomains and their There is shifts could also be important. Prepa­ relationship to calcium transients in isolated snail impressive neurones. J Physiol 538, 371-382. rations in which either large calcium evidence that Somjen GG & Tombaugh GC (1998). pH fluxes and concomitant high levels of modulation of neuronal excitability and central derangements PMCA activity are known to occur (eg nervous system fuctions In pH and brain function, in nitric oxide (ed. Kaila K & Ransom BR), pp. 373-394. New cochlear hair cells) or where moderate York: Wiley-Liss. (NO) occur in calcium fluxes occur in regions with Thomas RC (1984). Experimental displacement of all of the little cytoplasmic volume (eg ciliated intracellular pH and the mechanism of its main cardio­ portions of olfactory receptors) are subsequent recovery. J Physiol 354, 3P-22P. vascular Tombaugh GC (1998). Intracellular pH buffering Roger Wadsworth both likely to show local pH shifts. shapes activity-dependent Ca2+ dynamics in diseases. This has Finally, there is also mounting dendrites of CA1 interneurons. J Neurophysiol 80, fuelled continuing interest and specula­ evidence that local pH shifts might 1702-1712. tion in the possibility that alteration in regulate calcium fluxes during Tombaugh GC & Somjen GG (1998). pH NO may be causative in certain cardio­ modulation of voltage-gated ion channels. In pH calcium release from stores. This is and brain function, (ed. Kaila K & Ransom BR), pp. vascular diseases, or that delivery of something that is currently making 395-416. New York: Wiley-Liss. additional NO may be beneficial in our MRC Co-op twitch. Trapp S, Luckermann M, Kaila K. & Ballanyi K. therapy. This evidence, though exten­ (1996). Acidosis of hippocampal-neurons mediated by a plasmalemmal Ca2+/H+ pump. NeuroReport 7, sive, is almost all indirect, being based Christof J Schwiening 2000-2004. principally on interpretation of end­ Department of Physiology Willoughby D. & Schwiening CJ (2002). Electrically organ responses to inhibitors of NO evoked dendritic pH transients in rat cerebellar University of Cambridge synthase, and the detection of by-prod­ [email protected] Purkinje cells. J Physiol 544, 487-499. Willoughby D, Thomas RC & Schwiening CJ ucts of NO metabolism. The develop­ www.physiol.cam.ac.uk/staff/schwiening (1998). Comparison of simultaneous pH ment of the NO microsensor provides a measurements made with 8-hydroxypyrene-1,3,6­ method for real-time measurement of trisulphonic acid (HPTS) and pH-sensitive 1 + I use H here to represent an acid equiva­ microelectrodes in snail neurones. Pflügers Arch NO concentration, and a symposium + lent, of course it could equally be H3O , 436, 615-622. was held at the European Society for + H5O2 and so on. Furthermore a move­ Zucker RS & Regehr WG (2002). Short-term Microcirculation 2002 meeting in synaptic plasticity. Annu Rev Physiol 64, 355-405. ment of H+ in one direction could equally Exeter (August 2002), to discuss the be a movement of OH- in the other direc­ Physiological measurement of NO using tion. For the sake of this article such electrochemical microsensors. differences should cause us little worry. At the symposium, Malinski described the initial concept of the NO 2 It does, however, require knowledge of microsensor and its subsequent devel­ the pK of HPTS and the approximate opment into a variety of configurations starting pHi. Of these two variable the suitable for particular applications starting pH is least certain, however the (Malinski & Taha, 1992). Devynck calibration is relatively insensitive to pH at described the advantages and limita­ neutral and acidic values. The formula is: tions of coated microelectrodes to (pH-pK) pH = log (F/F0) – log (1-(F/F0-1).10 ) monitor NO from cultured vascular 20 PN FEATURES

has heard of, but never seen, an elephant – they know approximately what it looks like and where it can be found, but they have little knowledge of its behaviour, its function, or how to make more of it (Figure 2).

Roger Wadsworth Department of Physiology & Pharmacology University of Strathclyde

Acknowledgement The symposium was supported by educational grants from the British Heart Foundation, the Wellcome Trust, World Precision Instruments Inc, Servier Young Investigator Awards, The Physiological Society and Pfizer Ltd. Figure 1 Simultaneous recording of NO concentration and relaxation in rat mesenteric artery. The artery ring was precontracted with noradrenaline and then acetylcholine was added cumulatively. Note that a small remnant of NO formation and relaxation remain in the presence of L-nitroarginine 100 µM (see Simonsen et al References 1999 for further details) Escrig A, Gonzalez-Mora JL, Mas M (1999) Nitric oxide release in penile corpora cavernosa in a rat cells (Pontié et al 2000). Mas described for differential pulse voltammmetry model of erection J Physiol 516 261-269. Kutzsche S, Kirkeby OJ, Rise IR, Saugstad OD (1999) the application of a NO microsensor to (Escrig et al 1999). Zhang et al (2000) Effects of hypoxia and reoxygenation with 21% and measurement of NO in vivo, using the described that characteristics of a 100% oxygen on cerebral nitric oxide concentration corpus cavernosum penis as a model commercially available series of NO and microcirculation in newborn piglets. Biol Neonate 76, 153-167. vascular bed (Escrig et al 1999). microsensors. Malinski T, Taha Z (1992). Nitric oxide release from a Kutzsche et al (1999) described the One example of the application of single cell measured in situ by a porphyrinic-based effects of hypoxia and reoxygenation NO microsensors in blood vessels is microsensor. Nature 358, 676-678. on cerebral NO concentrations in pigs. shown in Figure 1. Piepot HA, Boer C, Groeneveld ABJ, van Lambalgen AA, Sipkema P (2000) Lipopolysaccharide impairs Delli Gatti described the effect of A ring of rat mesenteric artery was endothelial nitric oxide synthesis in rat renal arteries. plasma lipoproteins on NO production held in a small vessel myograph in Kidney Int 57, 2502-2510. in cultured endothelial cells (Vergnani Krebs solution. A NO microsensor (30 Pontié M, Gobin C, Pauporté T, Bedioui F, Devynck J et al 2000). Stankevicius et al (2002) micrometres diameter) was inserted (2000) Electrochemical nitric oxide microsensors: sensitivity and selectivity characterization. Anal Chem used NO microsensors to show that into the lumen using a micromanipu­ Acta 411, 175-185. nitric oxide release in arteries from lator. Relaxation of the artery with Simonsen U, Wadsworth RM, Buus NH, Mulvany MJ renal hypertensive rats is impaired. acetylcholine was accompanied by NO (1999) In vitro simultaneous measurements of relaxation and nitric oxide concentration in rat There was also a workshop oriented formation, detected at the superior mesenteric artery. J Physiol 516, 271-282. to practical applications and technical microsensor. The concentration of Stankevicius E, Martinez AC, Mulvany MJ, Simonsen questions, which generated a lively and NO detected was approximately 10 nM U (2002) Blunted acetylcholine relaxation and nitric release in arteries from renal hypertensive rats. spontaneous discussion. Boer outlined at maximal relaxation; however, the J Hyperten 20, 1571-1579. many pitfalls but ultimate success with endothelium has a considerable Vergnani L, Hatrik S, Ricci F, Passaro A, Manzoli N, the measurement of NO measurements reserve capacity and higher concentra­ Zuliani G, Brovkovych V, Fellin R, Malinski T (2000) in isolated arteries (Piepot et al 2000). tions of acetylcholine generated more Effect of native and oxidised low-density lipoprotein on endothelial nitric oxide and superoxide Gonzalez-Mora described equipment NO, over 20 nM. The NO synthase production. Circulation 101, 1261-1266. inhibitor L-nitro-L-arginine 100 µM Zhang X, Cardosa L, Broderick M, Fein H, Lin J (2000) caused a very pronounced, though An integrated nitric oxide sensor based on carbon fiber electrode coated with selective membranes. not complete, block of NO formation Electroanalysis 12, 1113-1117. and relaxation. Adapted from an article published in the British Anyone interested in the technique Society for Cardiovascular Research Bulletin or applications is welcome to contact R M Wadsworth for further informa­ tion ([email protected]). Our present state of knowledge of Exeter Cathedral reproduced with permission © Exeter Cathedral reproduced Figure 2 13th century carving of an elephant in the role of NO in cardiovascular Exeter Cathedral disease can be likened to someone who FEATURES PN 21

Labouring Lord An interview with Professor Robert Winston

career in research, given problems with relatively poor stipends and salaries, funding, short-term contracts and a poor career structure. ‘I think the prospect for young scientists isn’t that bad. If you went round this laboratory, where there are 24 young scientists on this floor, most of them female, I think most of them are engaged and excited by what they’re doing and not depressed at all. I think they feel very vibrant, actually. There are major problems within the universities because they’re not prop­ erly funded, but there are some indica­ tions that the government is taking that on board. ‘It’s not the PhDs and the young scientists who are depressed,’ he adds. ‘I’d say it’s the senior ones. The envi­ ronment that they’re having to admin­ ister is a difficult one,’ Winston says, adding optimistically: ‘But that will change, I suspect.’ On his bookshelf is a card, a detail of Michelangelo’s The creation of Adam. It seems particularly apt in Winston’s office. Many ask whether he feels like

© Institute of Biology 2002 God, bringing life into the world, a Professor Robert Winston comparison he dislikes. ‘No. I don’t believe that I’m a creator I was just nine years old in 1978, the looking a tad vexed behind his trade­ of life. I’m merely an agent that helps year Professor Robert Winston and his mark glasses and moustache. He shakes life into the world a bit. I think repro­ team created the world’s first ‘test-tube my hand then hurriedly runs through ductive physicians who start thinking baby’. Twenty-four years later, over a his gruelling schedule with his PA. of themselves in grandiose terms – and million test-tube babies have been born When it’s my turn, he apologises if I think some of my colleagues do – are and I am sitting in Winston’s office, he seems distracted and irked, which likely to do a disservice to themselves surrounded by a collage of hundreds of he clearly is: he has to fly to the States and to their patients. photographs of children, children, chil­ the next day to give a talk and his ‘What this subject ought to show dren: mostly newborns, some minus­ laptop has crashed. On it is the only very clearly clinically to its practi­ cule in incubators, several smiling copy of his talk, he explains, and he tioners is how fallible we are. There­ toddlers, and some now as spotty still has a hideously crammed schedule fore, above all, there should be a sense teenagers – all of whom would not be to get through today. of humility about it, because most of here if Robert Winston had not had a I thus drop the question about his the time we find we aren’t actually hand in their conceptions. views on the new company set up to helping. It’s a difficult technology Moments later, I am led to his other provide sperm for lesbian couples, Man which doesn’t work an awful lot of the office, this one in a slick, modern and Not Included. Instead, I ask what advice time, and that ought to keep us more much brighter building. Professor he has for undergraduates thinking humble than we sometimes are.’ Winston soon appears, well-tanned but about embarking on an academic It certainly is a difficult technology. 22 PN FEATURES

According to the Human Fertilisation are important. A BBC 1 television Science and the media and Embryology Authority (HFEA), IVF programme that’s watched by five When I ask how well the British media success rates for 2000/2001 averaged million people should be as just as is reporting science issues responsibly, a 25.1% for women aged under 38 and valuable as writing an esoteric book long, thoughtful pause indicates his 21.8% for those aged 38 and older. Still that sells 3000 or 4000 copies but is ambivalent feelings. While he extols when you compare that to Nature’s extremely well written and wins a non­ several broadsheet science journalists, own surprisingly low success rate, fiction prize.’ and science writers such as Steve Jones, which averages about 15%, it is no The public’s distrust of scientists has he excoriates much of the rest. wonder that some regard his work as remained fairly constant for years. ‘It’s extraordinarily variable,’ he says, god-like. Issues such as the BSE scandal, the foot­ chin in hand, gazing out of his window Obviously, successful cases bring and-mouth epidemic, concerns over towards Wormwood Scrubs prison. much ‘personal satisfaction’ to the use of animals in medical research, ‘Sometimes it’s appalling. Frankly, the Winston, but he stresses that unsuc­ GMOs, and the ongoing debate about way BSE was reported was abysmal. The cessful cases have their own particular the MMR vaccine have recently fed this way much of cloning was reported was and important value as well. distrust. Winston feels that this distrust also quite dreadful, prurient. ‘One can get a tremendous amount is largely the scientific community’s ‘There’s good and bad. But there’s of satisfaction from helping people own doing. certainly clear evidence that we need through failure. A lot of my work is ‘More scientists are engaging a bit improvement. The difficulty is not so actually doing that – knowing one’s better than they did, but we still tend much the science writers as the limitations, trying to persuade people to present ourselves as being very newsprint journalists and the news not to go through treatment, trying to certain, whereas science is about conveyers on television. It troubles me help them to take that decision. Trying uncertainty. We still are not prepared deeply that, for example, it’s impossible to make that a positive experience can to really understand why members to have a serious scientific discussion be the most challenging aspect of of the public have difficulty with on Newsnight although science regu­ reproductive technology therapy. It can issues such as the perception of risk. larly comes up on Newsnight. It’s got be very, very rewarding and can be I think there’s more to be done with to the stage now where they ring me immensely beneficial to the couples the science environment than with and invite me to come onto the themselves. One shouldn’t overlook the public environment. We still talk programme and I generally don’t that, I think it’s very significant.’ about the “public understanding of because, frankly, I’m not at all science” when it should be the scien­ convinced that they seem capable of Science and communication tists’ understanding of the public really understanding why scientists feel As is apparent through his television that’s the real issue.’ that they’re not presenting scientific programmes and his work in the House Winston said in a recent interview work in a way that is at all reasonable. of Lords, Winston is strongly that ‘transgenic humans’ was ‘the real To present science as entertainment committed to improving communica­ debate’ that needed to be debated. may increase your viewer figures, but it tion between scientists, politicians and When I ask him to elaborate, he doesn’t actually help the issues that the public. While he feels that scien­ dismisses that specific comment, but you are discussing.’ tists are taking positive steps in points out that the entire GM issue is engaging more with the public, he one that needs to be discussed and Science, ethics and believes that more effective methods communicated more effectively. embryonic stem cells should be embraced more often. ‘We’re not handling the issues of GM Despite being distracted by his laptop ‘I think that scientists are still a bit in general very well. I don’t just mean at times, glancing to see if it’s rectified dismissive of the more popular in humans, but in general. I think itself, Winston is an engaging inter­ approaches to science. They still think there’s a huge misunderstanding about viewee. He is articulate, intimidatingly in a very cerebral fashion about how it can be controlled, the relative erudite, and witty – but also occasion­ science, they still express themselves good it can do, and so on. I think ally prickly. very cerebrally and they still are rather transgenic technology has already Sticky questions of religion and dismissive of, for example, trying to do offered a great deal to human and ethics in scientific matters, such as things on BBC 1 or writing columns in animal biology, and could offer a great embryonic stem cell (ESC) use, clearly The Sun. In my mind, that’s almost the deal more. But if it’s not really under­ ruffle Winston on this occasion. When most important end because that’s stood, then I think that’s another I ask him whether he has an opinion as going to get to the biggest public, it’s example of an area where there needs to when human life becomes a human going to get to the people who actually to be better communication.’ person, he grows frustrated and impa­ FEATURES PN 23

tient. While expressing deep respect for to work. I think there are much more about communicating, in a rather many central values in Catholicism, important things. Why have interna­ simpler way than we generally do, Winston finds this debate particularly tional regulations on cloning but not what we expect to achieve from our Catholic, and particularly perplexing. on stem cells or transgenic animals or research. I think science is often seen as ‘I am puzzled by the concentration animals in research, or human medical a rather esoteric pursuit for the benefit on the definition of the beginning of research? I think cloning should be of a few people rather than for the life. I find it difficult to understand seen for what it probably is: a dead benefit of society as a whole.’ how a fertilised egg, which may be end that is of no great value, and a fertilised abnormally and have no couple of pompous and rather Reluctant celebrity possibility of being viable, can be bombastic individuals, one American, The scope of Winston’s work as a equated with a born child. And I have one Italian, who make periodic researcher, clinician, a medical media no understanding of how a fertilised announcements about how many chil­ celebrity and a Labour Peer who egg, which has only a 15% chance of dren they’ve cloned.’ recently chaired the House of Lords becoming a viable child on average, Select Committee on Science and Tech­ can be regarded as being inherently so New Year wish list nology is enviably exciting. While he valuable that you would not be When I ask Winston to comment on admits somewhat ruefully that ‘sitting prepared to pursue improvements in what issues the UK biosciences need to in a laboratory would be the most satis­ human health, save the mother’s address in 2003, he dwells silently for fying thing to do,’ I ask him whether health, save the mother’s life, if neces­ several moments. he enjoys the celebrity status that his sary, in preference to that embryo.’ ‘My main concern is the Medical work has brought him. Those who condemn the use of ESC Research Council. I’m rather concerned His reply – and not the first time in lines on ethical grounds often cite that the institution of collaborative my interviewing him – seems brusque scientific advances in adult stem cells grants and the abandonment of a and catches me off-guard. However, I as an additional reason for halting their policy of having project grants has, in realise that such replies reveal a funda­ use. While adult stem cell research may many ways, not always been helpful; I mentally humble and humane streak show their surprising multipotency and think it’s resulted in the MRC actually to Robert Winston. While he obvi­ therapeutic potential, it’s early days yet narrowing and reducing its ously derives immense pleasure from and Winston cautions against scrap­ constituency, and therefore reducing its his media work and fulfils the role ping ESC research. influence over medical research in aptly, it is secondary to why he does ‘The truth is that there isn’t enough Britain. I think that one of the issues it, and his surprisingly serious reply information to choose and it would for the new Chief Executive will be to reaffirms that streak: be foolish to abandon one branch of try and review whether or not it might ‘I don’t think I understand the word research in favour of another before not be better to spread the money “celebrity”. I don’t approve of “celebri­ either is much more than fledgling slightly wider, given that there was a tisation” at all. That’s not what I try to form, given the fact that ESCs are slightly increased budget. achieve. The reasons for the profile are being wasted at the present time. ‘Another issue remains with the because I think that there’s a great need The push should be to try to use them MRC: it would also be quite good to see to present the value of science – and maximally, to try to see whether or a bit more transparency about the way unless we do that we’re doomed. If not there are certain advantages in grants are applied to review. I think there’s a spin off of being slightly better using them.’ that might be possibly true across UK known as a result, that’s a penalty I When we touch upon human science generally. Whilst peer-review is have to accept.’ cloning, a contemptuous laugh encap­ a very good thing, I think that some­ sulates his dismissive attitude towards times the mechanisms aren’t as trans­ those who claim to be on the brink of parent as they might be. successfully cloning humans. Does he ‘I think there are so many issues feel we need internationally binding really. I think we’re not doing enough regulations in place to control it? to explain to the public and politicians ‘I can’t get worked up about cloning. why this investment in science is I think it’s an issue that is irrelevant. needed. To most people, for example, I just think we’ve wasted so much the letters BBSRC and MRC are mean­ time getting outraged and engaged by ingless; people don’t know what they Bill Parry This interview contains extracts from Humane a technique which is of no real value stand for or what these bodies are Instinct, published in Biobits (November 2002), the to anybody and, actually, is not likely doing. We should be doing much more newsletter of the Institute of Biology. 24 PN FEATURES

A physiologist digresses about piping As a physiologist in Scotland, Geoffrey Walsh cannot miss the potentialities for the study of pipers and piping

There are a number of different types ill, has been made possible to a large of bagpipes (cf Figure 1); when the extent by the extraordinary control by word is used without qualification it the brain of the hands. invariably refers to the Great Highland Five years ago, whilst working with Bagpipe of Scotland. The sound is Dr Julian Toms at the Health Centre in continuous, there are no gaps; by Portree, Isle of Skye, I met Dr Angus contrast the Northumbrian pipes are MacDonald, a general practitioner and usually played ‘staccato’. The fingers of a piper of distinction, I was amazed Geoffrey Walsh a piper can move with extreme that the errors he made on my instru­ rapidity, the commonest grace note, ment were much smaller than those I ‘High G’, is made by flicking the left had obtained on medical students in index finger, its hole is vented for Edinburgh. Intrigued I went to the merely about 20 ms. Piping Centre in Glasgow where the For many years I worked in the Edin- director, Roderick MacLeod, introduced burgh Medical School and was espe- me to six skilled pipers. Similar results cially interested in muscles, the way were obtained – the errors of the pipers they work and the way they control were clearly less than those of the movements (Walsh, 1992). A physiolo- students. Bit by bit I added more data gist in Scotland cannot miss the poten- and made measurements on a total of tialities for possible studies of pipers and 12 pipers, 127 medical students and 28 piping. In my youth I had played no young adult classical musicians instrument but belatedly, at the age of studying at the Birmingham Conserva­ 47, took up the flute; the basic fingering toire with the help of Dr Peter Johnson. was not difficult to learn. I found that The errors of the pipers were easily the moving two or more fingers in the same lowest (Figure 3). direction at the same time normally was The instruments played by the not difficult but moving two fingers in students at Birmingham were a mixed opposite directions, as in a ‘fork’, could group; I did not succeed in getting an be harder. I could find nothing written adequate sample to evaluate the skills about this in the scientific or medical of different types of classical musicians. literature so built an instrument to Two years ago I found that in Hanover make measurements; I have been a there is an Institute for Music Physi­ radio ham since my youth and like ology attached to a Hochschule where Figure 1 Irish war pipes. dabbling in electronics.1 The person young adults train to reach a high stan­ A 16th century woodcut by John Derrick (Flood, 1911). was asked to touch one metal button dard as performers (Walsh 2001). It is Figure 2 A study of the movements of the with one finger and at the same instant the – Institut für Musikphysiologie und two index fingers. Touch sensitive circuitry lift another finger from a second Musiker-Medizin, Hochschule für was used. button (Figure 2). With Musik und Theater, Hannover. URL­ two thumbs and http://sun1.rrzn-user.uni-hannover.de/~n3x3mphy/ eight fingers there pages/english1.htm are many permu- I got in touch with the director, Dr tations and combi- Eckart Altenmüller, and having by then nations of movement computerized my arrangements, flew are possible, this out with a laptop and other apparatus allows for great versa- and spent two weeks measuring a variety tility in hand control. of different types of finger movement The human dominance in over 60 musicians. On returning to of the world, for good or Edinburgh I ran the same tests on FEATURES PN 25

medical students who had never played The pipe is an an instrument, on pipers at the Army extremely responsive Index finger flexes, Middle finger flexes, middle finger extends index finger extends School of Bagpipe Music and of the instrument. Fric­ Highland Regiment and on two tional losses between Right members of the Glencorse pipe band. the moving air and The numbers of instrumentalists and the wall of an instru­ non-musicians is given in the Table. ment are related On all of these persons 14 tests were inversely to the cube run, the fingers moving in contrary of the bore. Thus a Left directions to the beat of a metronome practice chanter with at 120/min. The easiest were contrary a bore of 5 mm will movements of the two index fingers, have about 55 times the most difficult contrary movements the ‘damping’ of a of the ring and little fingers. It is flute with a bore of intended to publish the full details else­ 19 mm. These losses increase with Figure 3 Means errors (ms) of conservatoire where. The data files on the computer frequency. Furthermore, of the instru­ students (unfilled), pipers (filled) and medical students (vertical lines). Bars = 1 S.E.M. were subjected to statistical analysis. mentalists I studied, only the pipers The results are summarised in Figure 4. normally play out of doors; reverbera­ tion as in a room or a hall will be absent include organ pipes, drones, etc) may INSTRUMENTALISTS number and will not mask imperfections in the fall into step by the transfer of tiny transition from one note to another. amounts of energy; there is ‘entrain­ Bagpipers 15 The sounds of the pipes are rich in ment’. Lord Rayleigh (1842-1919) Woodwind players 13 overtones, a noteworthy study is that found that when two organ pipes were Violinists 11 of MacKenzie (1995). The harmonics of fed from the same wind chest the notes the drones extend to 10,000 Hz, the became identical. When the reed on Pianists 23 limit of my instrument, and may have one of the drones of a pipe closes, the Accordionists 10 components too high for the human pressure in the bag will rise and if Non-Musicians 36 ear to hear. This rich spectrum will give another reed is nearly opening it is

Table Numbers of instrumentalists and non­ the listener a multitude of information likely to do so at once; So far I have not musicians studied about changes of pitch. Piping being in come across measurements of the pres­ Scotland highly competitive, a good sures in the bag of a bagpipe; the situa­ The errors were nearly always of one judge may be expected easily to recog­ tion with the pipes is more complex sort in both the Birmingham and the nize unusually fine skills. than in Rayleigh’s observations because Hanover studies. When a person The pipes have two tenor drones there are four rather than two oscilla­ attempts to touch one disc and simul­ both tuned to ‘A’, a base drone tuned tors, three drones at running sensibly taneously to lift another finger it is to ‘A’ an octave below, ‘Low A’ on the stable frequencies, and the chanter of usual for the finger coming down to chanter is an octave higher than that of the notes which are constantly reach its target before the other starts the tenor drones and ‘High A’ is two changing. to rise, there is ‘overlap’ (cf. Walsh, octaves above the notes on those What happens to the breathing of 1997). For a while both fingers are in drones. The acoustics are complex; how pipers? To supply the three drones and contact with the discs. Occasionally the is it that after careful tuning the chanter considerable air flow is needed. finger coming down has not reached its chanters lock together? Even with the target before the other has lifted off, best ear a piper will not be able to reach Figure 4 Overall means for overlap times. The pipers both fingers are for a while in the air, the accuracy of a caesium clock. A have lower errors than any of the other groups. There were 15 pipers, 13 woodwind players, 11 violinists, there is a ‘gap’. Of the data for Figure 3 Dutch mathematician, Christiaan 23 pianists, 10 accordionists and 36 non-musicians. only that for the pipers in the lower Hygens (1626-1693), noted that when All were right handed young adults. (Bars = 1 S.E.M.) right panel is negative, indicating a two clocks were gap. With a woodwind instrument such mounted on the imperfections lead to the length of the same wooden board ‘resonant air column’ being for a while the pendulae swung incorrect and unless the error is small at identical rates. the music, if being played legato, will Sometimes oscilla­ be impaired. tors (this term can 26 PN FEATURES

When inexperienced persons Cannon’s Peak – a challenge to Society members breathe to the same extent as pipers they become dizzy; some neophytes A mountain named after a physiologist – do you know of may faint – experienced performers other geographical features named in this way? are free of these effects. There is a great deal of interest A year or two ago I was contacted by and there, at the head of the Lake, was in the science of sport; athletes Professor Owen Wade regarding the Mt. Cannon. Because there were two Goat believe the information helps adventures of Walter Cannon, best Mountains in the region another name for them improve their performances. known for his gastroenterological work, one of them had to be found, and the By contrast there is an almost but who, with his wife Cornelia and a government had given our name to the one complete dearth of information French-Canadian squatter named we had been first to climb.’ about the ergonomics of playing Comeau, was first to climb a local mass The area is phenomenally beautiful any musical instrument, a curious previously called Goat Mountain on 17 and unspoilt and it must have been a anomaly. The equipment used July, 1901. This may have been during great thrill for the Cannons to have the by athletes is for the most part Walter and Cornelia’s honeymoon and mountain, albeit a relatively small one, simple, and special study is unnec­ could have ended in disaster, since on named after them. As Professor Wade essary. By contrast the physics of their way back they were almost killed says at the end of his letter “I do not musical instruments is complex; by a landslide: ‘we saw a huge rock come know of any other geographical feature many fine papers may be found in rolling off the top of the mountain… named after a physiologist [or even a The Journal of the Acoustical Society followed by a continuous stream of small physiologist’s spouse, Ed.] – I expect of America and Acustica. stones which poured on the very spot where there are some and perhaps publication we had been eating our lunch’. will reveal others known to members of E Geoffrey Walsh It seems that Walter and Cornelia the Society!” [email protected] were in what is now Waterton-Glacier So there’s the challenge, are any International Peace Park by Lake other geographical features named after 1Call sign GM4FH McDonald in Montana when they physiologists? Please tell us if you know spotted Goat Mountain. They were told of one. Whatever it is you don’t have Acknowledgements it had never been climbed, so off they to climb or swim it or whatever, unless Thanks are due to the numerous people who went with hobnail boots, backpacks of course you actually want too! acted as subjects and to Mr Robert Gibbon for drawing Figure 2. and minimal other gear. After a fairly hard climb, with Walter getting stuck Bill Winlow References in a crevice at one point, they worked Editor Flood WHG (1911). The story of the bagpipe. their way up a narrow shelf on the bare Walter Scott, New York. mountainside, up a difficult scree and Quotations in italics are from : Walter Cannon (1945). Gibson TM (1979). The respiratory stress of The Way of an Investigator. Norton and Co. Inc., New playing the bagpipes. J Physiol 291 24P. thence to the top. The views were York. The book is difficult to find, but Professor Wade MacKenzie AC (1995). Some recent magnificent with snow-capped peaks, found a copy in Birmingham University library. measurements on the scale of the Great Highland glaciers and lakes. That night they Bagpipe. Proceedings of the Piobaireachd Society Conference,xxii. Unpaginated. made it back to their camp and next Walsh EG (1992). Muscles, Masses and Motion. morning were awakened by a MacKeith. Cambridge University Press, horseman with a string of pack Cambridge. animals. He was working for the US Walsh EG (1997). Synchronization of human finger movements: delays and sex differences Geological Survey and had tried to with isotonic antiphase motion. Exp Physiol 82, reach the top of Goat Mountain a few 559-565. weeks earlier. They told him of their Walsh EG (2001). Musicians and physiologists . adventure and he took their names. The Physiological Society Magazine 42. 8-9. Walsh EG (2003). Scientific tests prove pipers Seven years passed and they were surpass all others in fingering. Piping Times invited to dine with a colleague in the 55(4), 21 et seq. Harvard Department of Geology, where Watson AWS (1979) Some observations on the they were introduced to a topographer respiratory effort of bagpipe playing. J Physiol 227, 3-4P. from the Geological Survey and recounted their tale to him. ‘A few days later the mail brought a beautiful contour map of the area of Glacier National Park, AFFILIATE NEWS PN 27

Suffering for science Keri Lee Page comments on the Cambridge neuroscience research centre inquiry

As 2002 drew to a close, passions were running high in usefulness of the experiments which the neurophysiology community, as an inquiry into they didn’t even bother to support with Cambridge University’s plans to build a £24m neuroscience scientific evidence’. This concern was research centre on the outskirts of Cambridge turned into compounded at the inquiry when it a public debate over the scientific validity of the animal was revealed that Cambridge Univer­ model paradigm. sity, acting in fear for staff safety, disal­ The planning inquiry, which began on 26 November, 2002 lowed any practising primate research Keri Lee Page was called after South Cambridgeshire District Council neuroscientist from testifying at the turned down the University’s original application on the trial. This left Sir Keith – Physician and Head of the grounds of public safety matters. Cambridge University Clinical School – wide open to claims The University had hoped to confine the hearings to from Mr Wald that he was ‘unable to say scientifically discussion of planning issues after the government-appointed whether the underlying science can be applied to humans’. planning inspector, Stuart Nixon, ruled that it was not within Suddenly, the planning inquiry had become a trial of all his gift to ‘hear evidence on public health, animal welfare or medical research: experimentation that ‘may or may not lead moral arguments’ in a pre-inquiry meeting on 16 September. to a cure…basically amounts to scientific dabbling’. Mr Wald Nevertheless, Mr Wald, who spoke on behalf of animal challenged. Sir Keith countered: ‘If you knew what the welfare groups – Animal Aid and the National Anti-Vivisec­ answer was, there would be no point in doing the research’. tion Society, which represents NatureWatch, PeTA, Uncaged Nancy Rothwell, President of the British Neuroscience and X-Cape – insisted that ‘the proposal is controversial’ and Association, supports the University, saying that non-human that ‘public anxiety is a material planning consideration’. primates ‘are the only other species with well developed Cambridge University proposed a 10,000 square metre frontal and temporal lobes…and complex behaviours cannot facility to house all its existing primate research that is be studied in lower species’. In opposition, Ray Greek, currently conducted over several geographically dispersed Medical Director for Europeans for Medical Advancement locations. Up to 60 world-class scientists are hoped to be and witness for Animal Aid, explained that while humans employed in the centre, which has already secured about and primates have many similarities on a gross scale, we £8m in programme grants from the Medical Research should now be ‘looking at the molecular and the genetic Council (MRC) and Wellcome Trust. The Prime Minister, level; the level that defines a species’. He added; ‘Similarity in Tony Blair, who believes that the work is ‘in the national structures does not imply similarity in function.’ The species interest’, backs the plans. Basic and clinical research into new differences that Greek alluded to, however, ‘tell us a great treatments for stroke, Parkinson’s disease, Alzheimer’s, schiz­ deal about the relationships between structure and function ophrenia and substance abuse will be performed. as they relate to our species’ responded Dr Matfield, witness In his proof of evidence, the academic witness for for Cambridge University. Cambridge University, Sir Keith Peters, said that the research In his proof of evidence, Greek called on drugs like Flosint facility ‘would rank with some of the finest centres interna­ and Opren which during tests on primates yielded good tionally’. Animal rights groups, however, felt that the appel­ results but which killed up to 61 people in human clinical lants could not rely simply on ‘an assertion of national need’ trials. Gill Langley, member of the Government’s Animal and accused the university of ‘intellectual arrogance’. Sir Procedures Committee and scientific consultant to The Keith replied that the national need for neuroscientific British Union of the Abolition of Vivisection (BUAV), agrees research is ‘self-evident’ and that its relevance is fully that ‘people are being maimed and killed’ because results assessed by a ‘particularly stringent’ peer review process. from primate experiments ‘prove misleading when extrapo­ In a joint statement, National Anti-Vivisection Society lated to humans’. In the inquiry Greek pointed out that in director, Jan Creamer, and Animal Aid director, Andrew Tyler, 1998-2001 ‘eight drugs were recalled [in the UK] because of said that the university made ‘anonymous claims about the side-effects that were restricted to women and not men’, a 28 PN AFFILIATE NEWS

result that primate testing could not have revealed. He also In addition to the strong resistance from animal rights referred to the major human diseases which he believes have campaigners at the trial, Cambridge University faced further so far been unaided by primate research, such as atheroscle­ opposition from the district council who called upon various rosis, cancer and stroke. ‘The abandonment of animal police officers to testify over the risks of increased ‘crime and models is absolutely vital for medicine to advance’, disorder’ from violent protesters, should permission for the concludes Greek. In an attempt to prove this point, Mr Wald facility be granted. Matfield testified, however, that since the drew attention to the Alzheimer’s vaccine (AN1792) from animal welfare groups campaigning against the proposal Elan Pharmaceuticals and Wyeth-Ayerst, which moved make up the less radical end of the animal rights movement, directly from successful mouse-based trials to phase II human the demonstrations are likely to be ‘less frequent, smaller and clinical trials in 2001, without any intervening primate less aggressive’. The council expressed support for the testing. Embarrassingly, Mr Wald was not aware that in proposal in principle but made it clear that another site must February this year the trials were halted after 15 patients be chosen. Despite the council’s offer, the University insisted developed severe brain inflammation; a fact that Sir Keith that the proposed site was preferred because of its close prox­ was quick to point out: ‘I think you will find you have shot imity to the Wolfson Imaging Centre and University complex, yourself in the foot Mr Wald.’ which would allow collaboration, and enable scientists to In cross-examination, Sir Keith combated Wald by calling move between multiple sites on a daily basis. ‘The whole will Greek’s ‘scientific standing’ into question: ‘the vast majority be greater than the sum of the parts if this proximity is would disagree with him’, he noted. ‘Dr Greek alludes to achieved’, said Sir Keith. ‘Complete facilities would also mean many instances where deleterious side-effects of drugs have that the amount of information gained from each experiment not been tested by animal screens. However,’ argued Sir Keith, will be greater…we could need fewer animals’, he added. ‘it is very probable that a much larger number of drugs with The University emphasised the disadvantage that the UK adverse side-effects have been detected by such methods’. will suffer if the centre is denied: ‘This could have a big nega­ The BUAV received permission from Nixon to show an tive impact on neuroscience in the UK and Europe’, says underground video during the inquiry that contains footage John Capitanio of the California National Primate Research captured by an undercover BUAV investigator who worked as Centre. The research would ‘eventually be conducted else­ a technician at a Cambridge University primate research where, and possibly in countries with less rigorous legislation unit. Although a Home Office investigation has already and lower standards of animal welfare’, confirms Rothwell. cleared the lab of cruelty charges, the highly emotive images It is easy for most to assume that scientists are testing on of marmosets showed seizures and mental suffering. BUAV animals in a real attempt to reduce human suffering, and made the point that for experimental results to be mean­ that we are indeed researching alternative methods. But is it ingful the primates must be stress free: ‘The stress to the worth double-checking occasionally? Do we really challenge monkeys is self-evident from the video’, said Natalie Lieven the animal model to ensure that it is still valid today, and on behalf of the BUAV. not a relic of earlier times? Could imaging techniques be BUAV and Animal Aid urged Cambridge University to used to replace some areas of invasive neuroscience? Is the build an animal-friendly neuroscience centre that makes full likelihood of scientific fruition high enough to outweigh the use of new and alternative technologies such as fMRI, MR, primate suffering? What is the destiny of primate research? CT and PET imaging methodologies, as well as Maybe the issue is not as cut and dry as we once thought. neuropathology and epidemiology. ‘There is considerable The inquiry, which ended on 8 January 2003, was ignorance about the uses of other methods as replacements’, concluded as Nixon compiled a report for the deputy Prime says Langley. ‘This seems to have its roots in a defensive atti­ Minister, John Prescott, who will be taking the final decision tude, conservatism and resistance to change.’ According to any time now. the University, neuroimaging will be a major focus of the From the balance of opinion apparent at the Cambridge planned facility. Sir Keith emphasised, however, that these Neuroscience Centre inquiry, it would seem that in the UK, techniques ‘complement animal research rather than substi­ at least, the future of the animal model is skating on thin ice. tuting for it.’ Sir Keith stressed that imaging is still too crude Keri Lee Page to answer many key questions: ‘It’s like trying to understand Department of Zoology a computer by looking down a microscope at a silicon chip.’ University of Cambridge LETTERS TO THE EDITOR PN 29

Cellular abnormalities in models of hours and is back to normal by 24 hours, while the context of findings in an appropriate septic shock and in clinical disease plasma TNF- peaks at one hour and is normal animal model of septic shock. Dear Editor by three hours (Gardiner et al 1995b; Waller et Philosophical issues al 1995). This puts into perspective the rodent In spite of the fact that the article by Reade Reade’s feature considers the extremely diffi­ data alluded to by Reade, and taken by him to (2002) is entitled Cellular abnormalities in cult question of the ethics of obtaining tissues indicate fundamental rat/human differences. models of septic shock and clinical disease: one from comatose patients in septic shock, but We have drawn attention to the dissociation example of how rats and humans differ, careful does not answer it directly, and suggests that between cardiovascular status and iNOS acti­ reading reveals an acknowledgement of the tissues obtained as a result of a necessary clin­ vation in the context of the possibility that need for animal experimentation in the final ical procedure may be worth studying. NOS inhibition could have detrimental effects paragraph. We believe the fact that this is not However, it is clear that the ‘history’ of such in patients with signs of a hyperdynamic circu­ flagged in the title, or in the subsequent four tissues is going to be extremely variable, even lation (Gardiner et al 1995b). Subsequently, paragraphs, is unfortunate. when obtained from the same ‘type’ of patient we demonstrated functional involvement of (e.g., those undergoing bowel resection Reade’s article raises several important physio­ opposing vasoconstrictor (Gardiner et al following large bowel perforation). In addition, logical, philosophical and political issues which 1995a, c, 1996a, b, c, 2001) and vasodilator many septic patients will not undergo such we consider here. While we agree with much mechanisms (Gardiner et al 1995b, 1999a, b) procedures, and it seems that there may be of what Reade says, we believe his comments with different degrees of contribution at almost as many different clinical profiles as need to be put into an appropriate context. different times during infusion of LPS (Gardiner there are patients in the ICU. This raises the Physiological issues et al 1996c), together with temporal variations knotty question of what it is that any model Before dismissing them, the strengths and in vascular sensitivity (Tarpey et al 1998). should be simulating. It is possible the answer weaknesses of the various animal models of These features are, where they have been is that we should have a range of models, clinical sepsis need to be considered. investigated, also seen in clinical septicaemia. representing the range of clinical cases. As a generalization, the majority of research On balance, then, we suggest that an appro­ Political issues into experimental shock has employed in vitro priate rodent model of endotoxaemia is able If we were members of the scientific arm of the methodologies, or in vivo studies in anaes­ to mimic many of the events seen in the clin­ BUAV, we would take the title of Reade’s article thetized animals given large bolus doses of ical situation, in spite of the latter being so as evidence that animal experimentation is not bacterial lipopolysaccharide (LPS) which cause variable in aetiology. worthwhile. However, as indicated above, this substantial hypotension, and death within a Reade also mentions the failure of clinical trials is not a fair interpretation. relatively short time (for comment see to demonstrate benefit from interfering with Reade’s article is also relevant to the politics of Gardiner et al 1995b); Reade’s article focuses actions of individual mediators in septic shock. anonymous peer review and, presumably by on these approaches. Although such models But this is exactly what would be predicted by coincidence, an article on this topic appears in have provided useful information about puta­ our rodent model. Thus, TNF- antibodies the same issue of Physiology News (Cain, 2002). tive mechanisms contributing to the develop­ have no effect on the cardiovascular sequelae We are all aware that, in these days of fierce ment of the shock state, they have failed to of LPS infusion in conscious rats, in spite of competition for funding and RAE grades, address, properly, the role of these mecha­ marked changes in plasma TNF- levels (Waller decent scientific behaviour has suffered, and nisms in the functional outcome. Nowhere is et al 1995). Moreover, treatment with anti­ anonymous referees are on the look-out for any this more striking than in the assumption that bodies to TNF- and IL-1 , at doses that material to support their offhand criticisms. the marked fall in systemic arterial blood pres­ abolish the haemodynamic effects of adminis­ If Reade’s article passed without comment we sure following bolus injection of LPS is due to tered cytokines, has no influence on responses are concerned that it might provide more widespread vasodilatation when, if you take to LPS (Gardiner et al 1998). We have pointed ammunition for those dark forces! the trouble to measure haemodynamics, it is out that it is feasible the antibodies do not clear the hypotension in those conditions must reach the sites of production and local action Terry Bennett and Sheila Gardiner be due to an acute drop in cardiac output of endogenous cytokines during LPS infusion, Centre for Integrated Systems, Biology and Medicine because there is little vasodilatation (Gardiner School of Biomedical Sciences and some support for this proposal comes et al 1998). University of Nottingham from the finding that inhibition of production Some time ago we were concerned about the of TNF- and IL-1 production with FR ability of bolus injections of LPS to simulate the 167653 does have a significant effect on some References Cain, M (2002) Referee! Physiology News 49, 25. effects of clinical septicaemia, so began to of the haemodynamic changes during LPS Gardiner SM, Kemp PA, March JE, & Bennett T investigate the possibility of replicating some infusion (Gardiner et al 1999c). (1995a) Enhancement of the hypotensive and of the cardiovascular sequelae of the clinical Finally, Reade refers to observations on arterial vasodilator effects of endotoxaemia in conscious rats condition by giving continuous i.v. infusions of smooth muscle from patients with septic by the endothelin antagonist, SB 209670. Br J a low dose of LPS for periods of up to 32 hours Pharmacol 116, 1718-1719. shock, showing increased heme oygenase-1 in conscious rats. This approach has allowed us Gardiner SM, Kemp PA, March JE, & Bennett T when iNOS activity was decreased. Interest­ to delineate the profiles of change in cardiac (1995b). Cardiac and regional haemodynamics, ingly, this is a very similar picture to that seen inducible nitric oxide synthase (NOS) activity, and the and regional haemodynamics (Gardiner et al in conscious rats infused with LPS for 24 hours effects of NOS inhibitors in conscious, endotoxaemic 1995b), and to demonstrate significant, but (Tomlinson et al 1998). rats. Br J Pharmacol 116, 2005-2016. transient, increases in tissue iNOS activity and So, we encourage Reade to continue his Gardiner,SM, Kemp PA, March JE, & Bennett T plasma TNF- levels. It is notable that, in our (1995c). Enhancement of the haemodynamic effects important clinical studies, but to place them in model, iNOS activity reaches a peak at six of NG-monomethyl-L-arginine by transforming 30 PN LETTERS TO THE EDITOR

growth factor- 1 in conscious, normal, but not mimic the human condition. Drs Bennett and References endotoxaemic, rats. Br J Pharmacol 116, 3042-3048. Gardiner have published many studies of one Reade, MC (2002). Cellular abnormalities in Gardiner SM, Kemp PA, March JE, & Bennett T rodent model of sepsis, which it turns out has models of septic shock and in clinical disease: (1996a). Effects of dexamethasone and SB Br J many of the features of clinical human disease. one example of how rats and humans differ. Pharmacol 118, 141-149. In the light of this, they write in defence of the Physiology News 49, 12-14. Gardiner SM, Kemp PA, March JE, & Bennett T (1996b). Influence of aminoguanidine and the validity of animal experimentation. They Reade, MC. & Young, JD. (2003). Consent for endothelin antagonist, SB 209670, on the regional appear to have missed the point of my article. observational studies in critical care: time to haemodynamic effects of endotoxaemia in conscious I specifically state that I do not ‘suggest that open Pandora’s Box. Anaesthesia, in press. rats. Br J Pharmacol 118, 1822-1828. animal experiments have no role to play. Gardiner SM, Kemp PA, March JE, & Bennett T Indeed, quite the opposite …’. (1996c). Temporal differences between the Should we press for open peer involvement of angiotensin II and endothelin in the My fundamental point was that animal and cardiovascular responses to endotoxaemia in cellular models are just that – models – of review? conscious rats. Br J Pharmacol 119, 1619-1627. human disease. Any model must be validated A selection of letters in response to the Editorial Gardiner SM, Kemp PA, March JE, Woolley J & against the disease it claims to mimic. It is only and Unbelievable (Physiology News 49, 3 & 25) Bennett T (1998). The influence of antibodies to by doing this that more accurate representa­ TNF- and IL-1 on haemodynamic responses to the tions of disease processes can be developed. cytokines, and to lipopolysaccharide, in conscious Dear Editor rats. Br J Pharmacol 125, 1543-1550. I congratulate Drs Bennett and Gardiner, who I think this idea of irate colleagues pursuing Gardiner SM, March JE, Kemp PA, & Bennett T appear to have developed a better model of one at meetings etc is and always has been a (1999a). Influence of CGRP (8-37), but not human sepsis using rodents than that in the red herring. If criticisms are properly justified adrenomedullin (22-52), on the haemodynamic bulk of the published literature. But surely they there’s not really a problem (and editors responses to lipopolysaccharide in conscious rats. can only claim their model is ‘better’ than Br J Pharmacol 127, 1611-1618. shouldn’t make a final decision until they’ve those preceding it in the light of studies – like Gardiner SM, Kemp PA, March JE, & Bennett T properly heard the debate). The current system mine – of clinical human disease? (1999b). Regional haemodynamic responses to actually allows and encourages poor quality infusion of lipopolysaccharide in conscious rats: Drs Bennett and Gardiner write of ‘Political refereeing because no-one has to justify them­ effects of pre-or post-treatment with glibenclamide. issues’, but there is also a political dimension Br J Pharmacol 128, 1772-1778. selves to the degree required in a open system. to our own research. As I briefly outlined in my Gardiner SM, Kemp PA, March JE, & Bennett T I say scrap it and have the entire system open. article, it is usually not possible to obtain (1999c). Influence of FR 167653, an inhibitor of TNF­ Papers should only be rejected when they are informed consent from patients with sepsis. and IL-1, on the cardiovascular responses to chronic demonstrably technically flawed or demon­ infusion of lipopolysaccharide in conscious rats. J Even gathering clinical information, let alone strably wrong in approach or interpretation. Cardiovasc Pharmacol 34, 64-69. biological samples, without consent, is highly With grey areas, we should probably err on the Gardiner SM, March JE, Kemp PA, & Bennett T controversial. UK Medical Research Council and side of publication. The final arbiter for science (2001). Effects of the novel selective endothelin ETA European Union guidelines recommend proxy receptor antagonist, SB 234551, on the is reproducibility and internal consistency and consent, combined with the need for retrospec­ cardiovascular responses to endotoxaemia in that judgement is not down to individuals, but tive consent from the patient. Unfortunately, conscious rats. Br J Pharmacol 133, 1371-1377. in fact emerges from the corporate enterprise. Reade M (2002). Cellular abnormalities in models of UK law does not allow proxy consent for septic shock and in clinical disease: one example of how research. If current European Union recommen­ John Lee rats and humans differ. Physiology News 49, 12-14. dations are introduced into UK law as it now Rotherham General Hospital Tarpey SB, Bennett T, Randall MD & Gardiner SM stands, essentially all critical care research in (1998). Differential effects of endotoxaemia on the UK will cease, as we have recently reviewed pressor and vasoconstrictor actions of angiotensin II Dear Editor (Reade, 2003). While this would obviously and arginine vasopressin in conscious rats. Br J Poor reviewing by anonymous referees is a impact clinician scientists, basic scientists such Pharmacol 123, 1367-1374. scourge of publishing! Here is one suggestion as Drs Bennett and Gardiner would then have Tomlinson A, Gardiner SM, Willis D, Ali J, Kemp PA, that may improve the system without Willoughby DA, & Bennett T (1998). Temporal and no yardstick by which to judge their improved completely getting rid of anonymity. spatial expression of the inducible isoforms of animal models of human disease. cyclooxygenase, nitric oxide synthase and heme I would suggest that papers be reviewed Drs Bennett and Gardiner appear concerned oxygenase in tissues from rats infused with LPS in the anonymously until acceptance. Upon accep­ conscious state. Br J Pharmacol 123, Supplement 178P that some might interpret my article as tance, the reviewers that recommended accep­ Waller J, Gardiner SM, Jose J, & Bennett T (1995). ‘concrete proof that animal experimentation is tance should be named under the authors: Lack of effect of TNF antibodies on the cardiovascular worthless’. Clearly this is not the case. In truth, ‘Recommended by xxx’. Reviewers who specif­ sequelae of lipopolysaccharide infusion in conscious through different experimental methods we ically suggested that the paper not be rats. Br J Pharmacol 116, 2487-2495. have both done exactly the same thing: accepted, or who were non-committal, would demonstrate that the ‘conventional’ animal (at their choice) be left off the list, or specifi­ models of sepsis are inappropriate. I hope the Michael Reade responds: cally listed as ‘Objections raised by xxx’ or next steps in this research will bring clinical Drs Bennett and Gardiner write at length similar to indicate their lack of support for and basic scientists closer together, in ever about my recent article (Reade, 2002), which publication. more successful attempts to model and then highlighted major discrepancies between the modify the response to sepsis. Only through What are the merits of this system? function of nitric oxide synthase in cells from this co-operation will our research be of • The otherwise thankless task that reviewers patients with clinical sepsis, and those from benefit to the patients in our hospitals. do can be acknowledged publicly. As a journal many studies of rodent models purporting to editor, I know that this issue is a problem. With LETTERS TO THE EDITOR PN 31

nothing in it for the reviewers, only the most Dear Editor journal for papers savaged by referees- perhaps conscientious citizens will accept review Thank you for your Editorial, the gist of which I J Physiol Rejects. After say five years, the impact assignments. fully support. To the argument that anony­ factors could be assessed to see where the • Reviewers who accept a paper can be cred­ mous peer review should go, I would add that: good papers found a home. ited with recognizing good work when they James Morrison read it. In time, the abilities of a good reviewer 1 We are supposed to live in a culture of trans­ Institute of Biomedical & Life Sciences -critical to the efficient publication of worth­ University of Glasgow parency and accountability but British science while science (and hence to the rate of does not currently subscribe to this ethos. progress of science) – will become recognized Dear Editor and acknowledged. 2 You mention the problem of prejudice and bias, but careless review is probably an even I read with great interest your article, and that • Reviewers who may be falsely accused of greater/more common problem, especially for of the irrepressible Mr Cain, on the subject of letting dross get through can be acknowl­ funding applications. Competitors are easily peer review. Having myself been only too edged for their reticence! identified, but damning remarks from referees frequently a ‘victim’ of what might be called • Reviewers who accept poor or flawed papers who have not bothered to check the literature over-subjective refereeing, I am broadly could (and should) be recognized for this, can easily pass unnoticed by those who make sympathetic with the idea of an open (i.e. non­ hence obliging reviewers to be more cautious the final decision. Often, reviewers are clearly anonymous) system of refereeing. Producing a about increasing the ‘piles of second or third not experts in the field (you can tell that from signed review of peers’ work certainly focusses rate papers’ that you note we all have to their comments) but that does not seem to the mind on the science involved and plough through! stop them expressing (critical) opinions. suppresses the temptation to let loose any prejudice one might feel. Colin G Nichols 3 Identifying reviewers would also help to Department of Cell Biology and Physiology identify ‘scientific networks/ syndicates’ I would also suggest that an open system Washington University School of Medicine might carry other benefits. For example, how 4 It is often claimed that it would be hard to many times have we been obliged to contact find anyone willing to offer a critical review. the editor of a journal to chase up tardy Dear Editor Under those circumstances, failure to find a referees? I’ve lost count too. I suspect that, in I was very happy to read your editorial in the referee (even from a list nominated by the many cases, the tendency of some referees to last issue of Physiology News. authors/applicants) could be an alternative sit on a manuscript for a few weeks (months?) justification for a rejection. Nevertheless, I doubt I fully agree with your point that refereeing might be reduced if the identity of the referee whether this would be exercised much. In my must be open; I do believe that the current is known to all concerned. experience, authors/applicants are extremely system of anonymity, which allows quite a grateful for VALID criticism of their work: it Another point, related to the above, is that of degree of manipulation, is simply saves a more public humiliation at a later date. deliberate delaying tactics or even – to put it dishonest and indecent. The journal I am bluntly – pinching other peoples’ ideas. One I await with interest the next installment of currently running (Cell Calcium) has had an cannot help but be a bit suspicious when, after your editorial. open refereeing procedure for the last 22 a review process lasting six months or more – years, and I am extremely happy with it. Clare Stanford and ending in rejection – an uncannily similar The purpose of peer review is, at least in Department of Pharmacology study is published by a ‘rival’ laboratory. Again, theory, positive, i.e. referee’s comments University College London I suspect that a more open system of reviewing should improve the quality of a paper, rather would lessen this kind of thing, or at least than turn it down. I have examples of papers Dear Editor make us feel a little less bitter when such ‘coin­ going through several rounds of refereeing, Your editorial strikes a chord. I agree that cidences’ do occur. which finally substantially improves the quality referees should put their names to reviews: Having said all this, the acid test would be: Will of the material. Moreover, whenever referees after all, this is done for book reviews. referees be happy to put their name to their decide to reject the paper it is always very The issue of irate colleagues would probably reviews? In a lot of cases, probably not. well documented and based solely on the be met by, instead of one line rejections, Human nature being what it is, etc. If this is paper’s scientific merit. So you have my referees indicating how the work might be the case, I suggest the responsibility – and it’s supportive voice! And the impact factor (IF) brought, in their opinion, up to a publishable a serious one – to ignore non-objectivity and system, when used for judging scientific standard. That being so, the journal should be prejudice lies with the editor/grant committee achievements of individuals, is a disgrace. The prepared to consider a resubmission. I find it chairman. As does a more proactive approach IF merely reflects the smartness of editor(s), disheartening that having gone down this to chasing up referees and, in general, making e.g. publishing one or two special issues per route, The Journal of Physiology just does not sure that the whole process of peer review is as year (which are essentially a collection of want to know. ‘clean’ as possible. It’s lot to ask, but it’s essen­ reviews) immediately increases the impact tial to ensure that good science is recognized Personally, I value the refereeing process factor as do invited reviews. as such and gets due credit whether it origi­ because out of every clutch of referees, at least nates in ***ford, ******bridge or ***field. Alex Verkhratsky one knows what he is talking about and makes School of Biological Sciences useful comments. Often, that person is the Len Best University of Manchester most moderate of the bunch. University of ***chester There might be a case for starting a low cost e­ 32 PN LETTERS TO THE EDITOR

Dear Editor other journals if rejected, but many of the chairman of granting committees, that anony­ I give my total support to the concept of grant same comments apply to journal refereeing: mous peer review of papers and applications is reviewers being named. There is a lot of rot the removal of anonymity would increase the absolutely essential. The proviso, of course, is talked about the need to ‘protect’ referees but objectivity of reviews, increase author satisfac­ that there must be at least two independent if referees provided their considered, argued, tion and reduce the need for repeated revi­ reviews of any submission, and that if the rational comments on an application, there sions, reformatting, delay to publication, opinions received are seriously divergent (or if would be no need for ‘protection’. etc.etc. The only non-scientific reason for one betrays any evidence of bias) that one or rejection should be lack of space in a journal, more further opinions be sought. This can, of On the other hand referees, scientists though we and that will presumably disappear as a reason course, occasionally cause delays in processing, are, are only human. We all have people we like as more publication is effected electronically. but does I believe provide the optimal method and to whom we wish to give a helping hand, for ensuring that ‘the cream will float’ and that and those whom we despise for one reason or I could go on since, like so many of us, I have inferior or trivial work will not. another. More importantly, perhaps, there is suffered at the hands of this antiquated system always the knowledge that the more grants one for too long, but I trust these comments are Congratulations on doing a fine job with the approves, the less money there remains for one’s helpful. I should be more than happy to News. comment further or in another forum if that own application. This is a greater problem in Hugh McLennan would help. I do think that the major societies the UK than in the US where far more funding Vancouver, BC, Canada is available. If anything, removing anonymity should lobby hard and collectively to get these reforms passed. may be viewed as a means to ‘protect’ referees Dear Editor against themselves from letting any such bias Trevor W Stone Responding to your recent Editorial in Physi­ creep into their assessments. An alternative Institute of Biomedical & Life Sciences ology News and Mark Cain’s comment, I offer would be to use ONLY referees who are not University of Glasgow some thoughts on the referee process. My first able to apply to that granting body, such as paper was published, in Nature as it happened, referees from abroad (though personal likes Dear Editor in 1957 and my most recent has just been and dislikes may still occur). Some comments from a lapsed and retired accepted by a different journal, so readers will I also feel that granting bodies should be fairer physiologist. see that I have been in the game for some in their appraisals. It is easy to criticize 1 Is there a problem? How many complaints considerable time. Now it happens that I work anything, or to suggest additional work (even about referees? What are the editors’ experi­ in two fields of physiology, related in concepts, though no project can answer all the ques­ ences and views? but with colleagues who do not overlap. In one tions), or alternative approaches, or to indicate of these fields I flatter myself that I am a bit of a 2 Refereeing is essential for the reputation of non-quoted references (ignoring space sage, in the other I am a very definite maverick. constraints) etc. in order to make an assessment the journal and of future authors The point that I want to make is simple, and is seem more negative than it really is on hard 3 Anonymity – yes. This allows frank views very clear to me from experimental evidence scientific grounds. Striking a balance is likely to without giving personal offence or conflicts that I shall not detail. Under the present be worse for younger reviewers who are often with funding or status. Any disputes should be system of anonymous referees the weight of keen to show off how critical and incisive they resolved by the editor and his advisory panel. the report is usually not on the science of the can be, whilst not seeing that despite all their He is there to protect the author and see fair work under review, it is on the reviewers’ detailed reservations, 80 per cent of the work play (not always easy as I know). perception of the team that carried it out. will be done well and the project as a whole 4 Would it help if the author was anonymous Maybe this is inevitable, now that science has will yield valuable data to the field. Granting to the referee? become much more competitive than it was bodies should be much more objective in 5 Book reviews are different; reviewers should when I started out. The RAE has not helped, seeing through this and making judgements be named. There is no obligation to an editor or nor has the awareness of the accolades that by separating true criticism of the scientific a journal; the author is not bound by scientific are available from the Nobel and other similar hypothesis or methods to be used from these conventions but is free to discuss and speculate systems. (Lest I be suspected of sour grapes I peripheral comments, and taking an overall as he wishes. Purchasers gain from knowing the mention that in the most recent RAE I was view of the value of the project irrespective of reviewer (his standing and foibles etc.) returned in a 5* department, though not a the amount of wordage used to criticize. This physiology department per se.) is especially the case when experienced Alan Sykes researchers with a major track and publication Walthwaite How, Chapel Stile People asked to review, often rather ignorant record are the applicants. All that may be Ambleside, Cumbria of the precise science involved, are none the needed are some constructive, helpful less very adept at sniping from behind covers, a practice that I was taught to regard as comments from the external referee rather Dear Editor than a critical assessment of the project and unsporting, except in trench warfare. Often I I have read with interest your Editorial applicant as if he/she were a first-year postdoc. think they are motivated by much the same comments in Physiology News on the question (There also needs to be far more caution thoughts as a dog defending its patch. Chari­ of peer review and would like to offer my though in assessing criticism of hypotheses, tably, one might suppose that this is because views even though, since I am now retired, since this may stifle novel, innovative ideas and they see the total science cake as limited, and they may seem a bit dated. challenges to accepted dogma.) that they therefore act unconsciously to limit It is my unequivocal opinion, having served the share of it that goes in directions that they As to papers, it is true that one can resubmit to both as an editor and as a member and do not personally approve. SOCIETY NEWS PN 33

Maybe it is only a minor irritation to need to select Staff changes tary. David has been the Society’s with care journals where one can be confident that accountant since August 2001 and one will receive fair referees. It is a talent that one Members of the Society may have has been effectively the deputy acquires with experience, though it means that one’s heard that our Chief Executive, Chief Executive since then except best ideas may be published where they are less visible Esther Williams, left us at the end when he was acting Chief Execu­ than one might wish. The major sadness of the situa­ tion is in the grant-awarding system, where new ideas of September 2002. This she did tive in the hiatus early in 2002. He and new techniques can be largely discounted in an for personal reasons and with the studied Chemistry at UCL then established field, unless they can be made to accord amicable agreement of the Execu­ trained to be an accountant. He with the pre-existing weight of received wisdom. This tive Committee after having been in has worked in both public and is bad for science itself, which advances through the post for five months. This had been private sectors but most recently revision or overthrow of paradigms that are founded an eventful time for the Society for a charity, the Red Cross. He has on sand though they may be widely accepted. during which detailed negotiations extensive financial experience and Can anything be done to reverse this trend? I believe took place with Blackwell’s (the has been a company secretary on firmly that the answer is to insist that all referees should new publisher for our journals) two previous occasions. be identified to all parties. The journal Cell Calcium, and considerable reconfiguring of Maggie will be well known to where this is done, is respected and publishes high­ quality papers. The Editor, Maynard Case, wrote to the Society’s staff occurred. many members for she has worked Nature (1996, 379, 292) in response to John Maddox’s The best way forward was for the Society for many years; even defence of confidentiality ‘the requirement to sign the debated at length by the Officers so some may not be aware that report, while reducing the invective, in no way lowers the and by Council. It was considered her PhD was in genetics. Her expe­ scientific rigour of the referees who, unable to hide that continuity and a period of rience in dealing with all things behind unsubstantiated generalisations, are forced to stability were a priority consid­ educational for the Society, her focus on the facts. Is that not what science is all about?’. ering that there had been three links with the British Association I understand that this would make it more difficult to Chief Executives over the previous and many of our sister societies find people prepared to referee, a point made by year, including a temporary one and her networking of contacts Maddox and others. Unless editors (and chairman of for over six months, and that make her well suited to take on grant-awarding panels) have the courage to disregard referees who are clearly prejudiced (however distin­ three other experienced members particular responsibility for the guished they may be) this is the only safe way of staff had resigned over the external affairs of the Society. The forward, in my opinion. In my quite long experience, Summer. Furthermore, a speedy establishment of the Biosciences very few editors are that bold, with the honourable resolution was thought to be Federation (of which the Society is exception of Sir George Radda. necessary. Consequently, two a founder member) makes it essen­ Gerald Elliott important decisions were made: tial for us to give a high priority to Department of Optometry and Vision Sciences firstly that the position of Execu­ this aspect of the Society’s work. Cardiff University tive Secretary would more aptly Lest more sceptical members describe what the Society required start thinking that we have more Dear Editor of its most senior employee; and bureaucracy than ever, let me I strongly agree that authors should normally be told secondly that internal appoint­ assure you that because of the the names of referees. When I act as a referee for a ments should be made to the increasing centralisation of the paper submitted to a journal, I almost invariably ask senior executive positions of the Society’s work and some internal for my name to be divulged to the author(s). Society. The positions of Executive reallocation of responsibility Andrew Huxley Secretary and Deputy Executive there will be one less post in the Grantchester, Cambridge Secretary (with particular responsi­ London office in future. bility for External Affairs) were

Dear Editor advertised internally and inter­ Dafydd Walters views were held at the beginning With very few exceptions I have signed all referees’ of December. The interview panel reports for the last 20+ years. I have had no problems International with enraged authors. Very often any criticisms I have consisted of two Officers and three make have led to a constructive dialogue. I think members of Council, one of the collaboration – anonymity is morally wrong in what should be an latter being on the Editorial Board ICSU statement open scientific community – but I have never had any of The Journal of Physiology. success in propagating this view! Perhaps, if you I am delighted to inform you At the Annual General Meeting of agree, you could help. that David Sewell was appointed the Society in Leeds in September John C Waterlow as Executive Secretary and Maggie 2002 there was some discussion 15 Hillgate Street, London Leggett as Deputy Executive Secre- about the universality of science. 34 PN SOCIETY NEWS

Specifically, the topic was the stance of fact that these statutes affect all scien­ The launch was supported by the the Society in the support of and tific disciplines, not just physiology. Physiological Society. The Biochemical collaboration with scientists working in Perhaps the Editor would be willing to Society, Society for Experimental Biology countries with which there may be publish articles expressing some of our and the British Society for Immunology some political disagreement or the members’ views in the next edition of support the website. action of whose governments were Physiology News. questionable. Comments from Maggie Leggett members indicated a very strong view Dafydd Walters that there was no place in the practice Research Defence Society of science for discrimination based on nationality, religion, ethnicity, gender, Speakers in schools 2002 has been a busy year for the politics, etc. The Society is affiliated database Research Defence Society (RDS). They through our membership of IUPS launched a new booklet (The Hope, the (International Union of Physiological Earlier in the year many people Challenge, the People), as well as main­ Sciences) to ICSU (International responded to my email regarding a UK taining their usual highly visible media Council of Scientific Unions) whose Life Science Committee (UKLSC) initia­ and parliamentary contact, and educa­ statutes contain statements with which tive to compile a database of academics tional programme. It was therefore our Society has agreed. It was proposed willing to give talks in schools. The data­ fitting that the programme for the RDS at the AGM that the relevant ICSU base, stored on www.biology4all.com is freely Annual General Meeting on 25 statute, number 5, be placed on the available and searchable. It has been November, 2002 included some of the Society’s website and our adherence to developed by Dr Peter Robinson, a finest speakers. Among them, Dr Simon it be reiterated. This has been done. member of the UKLSC Education Group. Festing, the Director of AMRC, gave an There was also a request that attention interesting insight into campaigning. be drawn to it in Physiology News. The He gave a very positive view of the statute is reproduced here. current state of in vivo research in this country, and felt that the anti-vivisec­ ICSU statute 5 tion movement was at an all time low. ‘In pursuing its objectives in respect of the However, he recommended building on rights and responsibilities of scientists, the current position, and stressed the ICSU, as an international non-govern­ importance of responding to media mental body, shall observe and actively Colin Blakemore (left) with Peter Robinson enquiries and inaccurate reporting. uphold the principle of the universality of The initiative was launched formally Tony Gilland, from the Institute of science. This principle entails freedom of at the British Association Festival of Ideas, painted a somewhat gloomier association and expression, access to data Science at the University of Leicester picture. He pointed out that the ever and information, and freedom of commu­ on 12 September, 2002. The Physiolog­ strengthening ethical and legislative nication and movement in connection with ical Society president, Professor Colin process in this country was suggestive international scientific activities without Blakemore, opened the proceedings, that scientists were guilty until proven any discrimination on the basis of such followed by a short talk by Peter. The innocent. He further argued that a factors as citizenship, religion, creed, polit­ event was publicised by the media the society which elevated the rights of ical stance, ethnic origin, race, colour, week before, and has gained significant animals over humans was inhuman. language, age or sex. ICSU shall recognize coverage since. After tea, our President, Professor and respect the independence of the The launch went well, and there was Colin Blakemore, spoke about mapping internal science policies of its National considerable interest from academics, the future of neuroscience. As ever Scientific Members. ICSU shall not permit journalists and members of the public. Colin was entertaining and easy to any of its activities to be disturbed by However, we are all aware that this is understand, describing the mapping of statements or actions of a political nature’. only the beginning of the project. More various activities to parts of the brain, speakers are needed to get complete and stressing the past and continuous The Guardian newspaper has published coverage of the UK. If you are inter­ need for animal experimentation. several letters and articles on this topic ested, you can register yourself on the Last, Professor Lord Winston gave the over the past few months. Discussion database, or email me for further Stephen Paget Lecture. Lord Winston and interpretation of this statute is details. Eventually we hope that every addressed the question of why as a unlikely to end soon given the current school will be aware of the scheme, and species we are so infertile, and also political unrest in the world and the they all have access to an academic. outlined the current hazards of IVF. He SOCIETY NEWS PN 35

In other words (Rule Two): •Tell them a story

And (Rule Three): • Keep it simple and EXPLAIN

A simple question Nothing very complicated there, we can all agree. Why are most research Unfortunately, in practice it doesn’t work out like that. symposia so dull? Experience suggests that many eminent scientists giving invited talks in national and international symposia have A couple of postdocs I know – let’s call them Ian and Matt – never heard Rule One. asked me this the other day. Well, evening actually, after a Instead, they adhere to ‘Professorial Rule 1A’. This is a re­ pint or three. But the next morning, as I stirred my breakfast write of Rule One as follows: soluble Aspirin, I got to thinking. It is not enough to stand up and describe a load of your Just why ARE most symposia – and plenary lectures, for experiments. Instead, you should stand up and describe at that matter – so dull? Duller than the average departmental least three separate loads of experiments, each enough for a seminar, if you ask me. talk on its own, all delivered at breakneck speed in your Let’s try and think of some reasons. allotted time plus 15 minutes.

Reason one: because of the subject matter – science. Furthermore, rules two and three should also be modified:

Not that science is dull. Professorial Rule 2A: Don’t bother telling a story. Anyone But it can SOUND very dull, if you describe it in a very worth your time and consideration will already know all the dull way. background, and all your previous work, so you should jump straight in with the incredibly fascinating minutiae. Now there are people in the trade who think that no piece of scientific data can ever be dull. To them I have only two And Professorial Rule 3A: In order to make it clear that you words – Asperger’s Syndrome. However, for the rest of us, I still have full command of the techniques your army of assis­ think we could agree that, talk-wise, the nitty-gritty of the tants use in the lab, you must keep it as complicated as science – the experimental data – is never going to be as possible and avoid unnecessary explaining. interesting to the listeners as it is to the speaker. This is Result: The audience will be awe-struck by how large your because the speaker was generally (although not necessarily) research group is (in order to churn out the huge volume of one of the people who actually planned or did the experi­ work you have described) and how cutting-edge your ments, and thus has a big personal investment in the data. research is (because they didn’t understand anything you But this brings us on to something important, namely: said). Thus you will have shown them that you are a BIG PLAYER. QED. It is the job of symposium speakers to explain their data. And yes, you could even say, to ‘sell’ it to the audience. No Quod erat disillusionem? matter how famous the speaker, and how big a plenary Now I don’t want to leave you with a completely negative lecture it is, they still have to make us want to listen. message, so I should say that there IS a simple way to avoid Or at least, they should. talks like this at symposia, or in plenary lectures.

Let’s summarize this as ‘Scientific Talk Rule One’: Don’t invite the people that give them to be speakers. • It is not enough to just stand up and describe a load of But that depends on the people who organise the your experiments symposia. Which brings me on to what I hope will be the You have to tell people what they are about, why you did next column: them, what they show, and so on, all without talking in Symposium organisers: the truth. impenetrable jargon – be it electrophysiological, Watch this space. neuroanatomical, molecular biological or whatever – or even worse, in abbreviations. Mark Cain 36 PN SOCIETY NEWS stressed the need for this kind of treat­ London, rose to the occasion Careers conferences ment to be available on the NHS, as admirably. Olga’s talk entitled Bone fit otherwise the commercial drive for life started with some pretty This year, The Physiological Society misplaces emphasis and in this case can shocking statistics, such as that one in took the lead in organising these lead to overuse of the potentially three women would be affected by annual events. They were held at dangerous super ovulation drugs, and osteoporosis, and one in 12 men would Sheffield University on 2 November, reimplantation of more embryos than suffer that same fate and end up with a Glasgow University on 16 November sense and science dictate. fractured hip, unable to walk properly and King’s College, London on 30 The Society continues to maintain again. The audience concentrated as November, 2002. They were attended strong links with the RDS, and to she explained ways of exercising to by over 600 students, of whom one support its activities. keep bones healthy and the implica­ third were postgraduates. There were tions of preventing bone decay. The Maggie Leggett more exhibitors than usual, with most ensuing debate was lively and Olga did of the major pharmaceutical companies well to deal effectively with some fairly sending representatives. The normal British Association sticky questions, for instance in rela­ programme of talks about careers in Festival of Science tion to HRT. research, science communication, clin­ Dawn Skelton, also from UCL, ical science and teaching were supple­ In 2002 at the BA Festival the Physio­ completed the programme. Dawn mented by talks on patent law and logical Society organised a session enti­ talked about falling over and the neces­ science sales and marketing. Feedback tled Health in old age. The overall theme sity of preventing this in the older from the students was positive, with was Science and the quality of life, and as population. Again there were alarming comments such as ‘Wicked!’ and the festival always attracts many retired statistics such as that one in three ‘Highly recommended’. If you are an people we were hopeful of a good audi­ people over 65 fall over every year and Affiliate and unsure of your next step, ence and lively discussion. the even more sobering thought than be sure to come along to one of the Despite one of the speakers, who will even during her talk, three elderly conferences in November 2003. The remain nameless, forgetting all her people in the UK would have died as a venues are still being decided, so look clothes, we were otherwise ready to go result of a fall. The results of the out for an email alert in September. at 9.30 on the morning of 14 September research presented certainly got the at the University of Leicester. The first audience going, and many people Maggie Leggett speaker was Professor Tom Kirkwood, stayed around afterwards to continue from Newcastle University, talking the conversation. about Aging and immobility. Tom’s Once again, in comparison with other Physiological and presentation was excellent, clearly areas, we attracted one of the largest Pharmacological in vivo explaining difficult concepts and the audiences. One speaker was subse­ techniques workshops progressive disintegration of telomeres quently hauled off for a radio interview, and the potential use of stem cells. another to a press conference and I These workshops are a joint venture Needless to say, the audience received requests for two of them for from the British Pharmacological responded well, questions were intelli­ the 5.30 round up of the ‘best of the Society and the Physiological Society, gent and discussion lively. festival’. We have featured good and were run for the first time during Next, Professor James Malone-Lee, contracts with the BA and are now August 2002. They developed from a from UCL, spoke about incontinence. respected as providing a valuable contri­ common worry about the ever­ James was hilarious, dealing with a bution to the festival. I can only look decreasing number of undergraduates potentially delicate subject with forward to 2003 and the University of with practical experience of this kind of humour and affection. He communi­ Salford. The theme there will be Sustain­ work, and the difficulty of attracting cated an unbelievable passion for the able science, and the Society session will PhD students with interest or ability in disposable nappy, and was also really be entitled Sustainable people, with talks the area. interesting, as he explained his on making new organs, etc. If you The workshops were generously personal crusade to stop the use of old would like to become involved, either supported by Pfizer, who share the crisp packets and dead mice as as a speaker or to attend, please contact same concerns. For the first year, absorbent materials, and explained the me as soon as possible. courses were run at Glasgow University reasons for toxic shock syndrome. and King’s College London. The It was a hard act to follow but Olga Maggie Leggett courses were heavily over subscribed, Rutherford, from King’s College and the maximum number of students SOCIETY NEWS PN 37

(27) accommodated. Feedback from Perhaps women all together are as Those interested in the London Met both the organisers and attendees was intimidating as men. SWAN should contact Louise Archer at excellent, and many students expressed Frances Ashcroft gave an excellent [email protected]. a wish to continue in the field. opening address, and described some These courses are extremely expen­ quite hideous barriers she had come up Maggie Leggett sive to run, and we are grateful to against on her way up the ladder, from Pfizer in the first instance and to other not being offered one job, to being pharmaceutical companies who are offered less money for another, purely Claire Martin promising support in the future. It is because she was female. Joanne Claire Martin, a medical student at hoped that the number of courses may Millington, a forensic scientist from Gonville and Caius College, who read be increased to three in 2004, and London Metropolitan, and Alison Adam Part II Physiology at the University of possibly extended to allow places for (IT, University of Salford), both gave Cambridge, was awarded the Science PhD students and post docs. The similar examples of discrimination. Engineering courses are advertised annually in In the discussion session after lunch and Tech­ October, and so if you are interested, several points were raised. Women nology Prize keep an eye on the website or email are attracted by science degrees – in for the Best alerts at that time, or contact me directly. fact many Members report their under­ Biology graduate classes are heavily female Student of the Maggie Leggett dominated. Women are also well repre­ Year (2002) by sented among applicants for PhDs. the World However, somewhere on the post doc Leadership Women in science – junior lecturer ladder they are leaving Forum on the what are the issues? science in their droves. Lack of family basis of an undergraduate research friendly career paths, lack of security in project she pursued with me in the When I took my PhD, I was one of the career and lack of ability to stay in Department of Physiology. only two women – both 1st year PhD one place were all agreed as reasons She examined structure-function students, in a department of about 25. why women leave. None of these is correlations in the triad structures, The attitude and behaviour of my male easy to solve overnight, although the made up of closely adjacent transverse colleagues varied, from mild flirtation Greenfield report has been welcomed (T)-tubular and sarcoplasmic reticular to surprise that a woman should even by Government and certainly raises (SR) membranes of skeletal muscle. want to start out on an academic the issue in the public eye. The organ­ These are believed to be the sites at career. I don’t think I suffered anything ising committee at London Metropol­ which T-tubular depolarisation triggers that could be described as harassment itan (lead by Dr Louise Archer) are in release of intracellularly stored Ca2+ or discrimination, but the over­ the process of into the cytosol of skeletal muscle whelming feeling that I was a fraud drawing up a during excitation-contraction coupling. and not expected by anyone to Charter based This involved a systematic study of the succeed, and a strong dislike of the on the ideas effects of extracellular solution tonicity competitive banter of the coffee room generated on amphibian muscle anatomy, in certainly did nothing to convince me during the particular quantitative measurements to stay in science. And in my position day. There is of the details of triad junction ultra­ now, the sex ratios of young physiolo­ definitely no structure following cellular volume gist symposia compared with that of longer a need changes. Three-dimensional recon­ the Council or Heads of Department for women to structions from successive electron meetings give cause for disquiet. feel isolated. microscopic thin-sections permitted Louise Archer, post-doctoral The Women and Science Day at The day such quantitative examinations of triad research fellow, London London Metropolitan University on 23 Metropolitan University culminated in anatomy. These results were compared October, 2002 was the first time I had the launch of with the propensity of the fully polar­ been in an academic environment that a new SWAN (Scientific Women’s Acad­ ized intact muscle fibre to show sponta­ was all female. The atmosphere felt emic Network). Contacting this or your neous Ca2+ release events as reflected in very different – there was one male local network is an excellent way to fluo-3 fluorescence measurements delegate but he ran off quite early, and keep abreast of new developments, and using confocal microscopy. the Vice Chancellor (male) departed form contacts that can help you in This combination of techniques after giving the opening address. difficult times. made it possible to test a hypothesis in 38 PN SOCIETY NEWS which the intramembrane dihydropyri­ New Cell to Man Other Society News dine receptor (DHPR)-voltage sensors normally suppresses the gating of SR Many Members will be familiar with the Changes in Aberdeen ryanodine receptor-(RyR) Ca2+ release careers booklet Cell to Man. It has served The telephone numbers for the Depart­ channels through the allosteric us well for many years, and persuaded ment of Biomedical Sciences in couplings between these molecules in lots of young people that physiology is Aberdeen, beginning 2730 now begin fully polarised quiescent muscle with the discipline for them. However, it was 5557, e.g. 273015 is now 555715. DHPR activation by membrane depo­ starting to look a little dated and so Old volumes of larisation relieving this inhibition throughout last year a small group have The Journal of Physiology thereby permitting release of intracellu­ been working on a new design. The most Peter H Hartline ([email protected]) has larly stored Ca2+. influential members of the group were mint condition, bound volumes of The Claire secured First Class Honours in Dr David Pepper, a biology teacher and Journal of Physiology from the late 1970s her Part II Tripos examinations and is former Member, and three of his sixth to 1984. If anyone needs these journals proceeding with her clinical studies in formers who could tell us what the or knows of libraries that would appre­ Cambridge University Clinical School. consumer wanted in terms of subjects ciate copies please contact him. The and images. Many Members also helped recipient would be expected to pay for Chris Huang with the text, including Rob Clarke, the boxes and shipping, but not the Malcolm Hunter and Ron Maughan. We labour to ship. are also very grateful to Pfizer for their Proceedings in 2003 support and particularly to Mike Collis. Young Musician of the Year At the Society’s Annual General Meeting The result (see below) is a booklet that Pianist Danny Driver, Physiological in Leeds on 11 September, 2002 a deci­ looks at alcohol and liver physiology, Society Undergraduate Prize winner sion was made to produce the final neurophysiology and class A drug abuse, (Cambridge), recently won the Radio 2 Proceedings issues of The Journal of Phys­ sports physiology and the use of Young Musician of the Year. iology in electronic format only. There­ cannabinoids in pain relief. There is also fore from 2003, there will be no printed a section with case studies of physiolo­ Any offers? issues of Proceedings. The abstracts gists pursuing a variety of different I am currently a second year undergraduate student studying biomedical sciences at King’s College London. from the UCL scientific meeting held careers. Early anecdotal feedback has My subject covers a variety of fields, but I am mainly from 17 – 20 December, 2002 will form been excellent, comments including interested in genetics, cell molecular biology and physiology. “riveting”, “eye catching” and “wicked”. the first issue to appear online only – I am looking for a summer placement in a science http://www.physoc.org/Proceedings/ If you would like to receive a copy, or orientated workplace. I do not mind what type of job it is, even if it is a voluntary position, as I would like the The decision to have online several for an open day, please contact experience to help me decide whether I am interested in publication only will not affect the me at the office. the experimental or theoretical aspects of my degree. The experience would also help me gain a deeper citability of these abstracts. These will Maggie Leggett understanding of my subject area. be citable as usual with the volume Shen Lin [email protected] number, but will be cited by abstract number rather than page number. The abstracts will be available, as usual, on the Society web page with addi­ tional links from The Journal of Physi­ ology website. They will continue to appear on the ISI Web of Science. Features available with Proceedings online include: • Email alerts when a new issue goes online • Abstract searching • Electronic author index • Author linking to other articles on Medline • Individual abstracts available online as HTML (browsing) and PDF (printing) OBITUARIES PN 39

Michael de Burgh Daly 1922 – 2002

was appointed as assistant lecturer many years past the normal retirement (1948-50) and lecturer (1950-54). In his age. Over the years he must have early days as a physiologist he was taught and influenced thousands of influenced by Lawrence Mount, Alfred medical, science and research students Schweitzer, Eric Neil and Chris all over the world. Many of his former Lambertsen in addition to working students are now themselves professors with his father. During this period he and leaders in their fields, thus his was awarded a Rockefeller Foundation influence on his subject has travelled Travelling Fellowship in Medicine far and wide. (1953-53) which he spent in Philadel­ He served on many committees and phia. He was then made a Locke was very conscientious in attending Research Fellow of the Royal Society them. He sat on the Ethical Committee (1955-58) in the Department of Physi­ at Bart’s but was also a member of the ology University College. At the young Personnel Research Ethical Committee age of 36 he was appointed to the chair MOD (Navy) from 1975, becoming of Physiology at St Bartholomew’s chairman in 1990. He also helped to Hospital Medical College and Head of supervise research in the Navy. He felt Department – a position he held from that by giving the Navy his expertise on 1958 to 1984 until he retired at the age the subject of diving and its implications Michel de Burgh Daly, MA, MD, ScD of 62. At this time Professor Spyer in man that he would contribute to the Cambridge, FRCP, Emeritus Professor of invited him to move to the Royal Free safety and welfare of this country. Physiology in the University of London Hospital School of Medicine in the and Distinguished Visitor Joint Depart­ Department of Physiology where he Research ment of Physiology Royal Free Hospital was to stay for the next 18 years. This His interest in the carotid body School of Medicine and University move allowed him to continue with his chemoreceptors and baroreceptors College, London from 1984 until his research without the burden of began early in his career. He was well death, formerly Professor of Physiology committees and university politics. He tutored by his father, Ivan de Burgh and Head of Department of Physiology was able to contribute to the depart­ Daly, who was an expert on the St Bartholomew’s Hospital Medical ment by teaching both the undergradu­ pulmonary circulation and they College, London from 1958 to 1984, ates and the research personnel who published papers together on this died suddenly on 1 March, 2002 at were able to take advantage of his subject in The Journal of Physiology in home aged 79, two months before his knowledge and experience. 1957, 1958 and 1959. After his father 80th birthday. He was a good and dedicated teacher retired from Babraham, they collabo­ Michael was the eldest son of the late who willingly gave many hours of his rated again in the 1970s, resulting in Dr Ivan de Burgh Daly, CBE, FRS, and precious time to teach others. He knew further publications. During the many was born in York on 7 May, 1922. He his own subject well and was meticu­ years of active research which was still was educated at Loretto School, Edin­ lous over the details and content of his continuing at the time of his death, he burgh and Gonville and Caius College, lectures. He made sure he was up to developed the theme of the peripheral Cambridge. He did his clinical studies date and would even contact experts in arterial chemoreceptors and respira­ at St Bartholomew’s Hospital, London their fields to get their advice about tory-cardiovascular integration which and graduated Natural Tripos Part I in any advances in the subject of his culminated in his opus magnus, the 1943, Part II 1944, Physiology with lectures. However, he was a perfec­ Monograph of the Physiological Society Pharmacology. He then became a tionist and would not suffer fools 46, with this title published by Oxford House Physician at St Bartholomew’s gladly. He could not understand why University Press in 1997. His research Hospital in 1947 before commencing other people could not do the things covered almost half a century and his his career as a physiologist, following he did so easily, and some of his thirst for the knowledge of his chosen in his father’s footsteps. research students found him a hard field led him to study many species of His first post in physiology was at taskmaster. He was still teaching and animals including seals in Alaska and University College, London where he lecturing up to the time of his death, monkeys in Australia. He had many 40 PN OBITUARIES

collaborators, some who came to him physiological life. He enjoyed being Research Grants as research students and others as invited to different parts of the world. During his scientific life he was experts who contributed by having One of his most momentous journeys supported by numerous grants from different skills. As a result of this was in 1975 when he travelled to such organisations as the Medical constant stream of theories and experi­ Alaska with his colleague, Jennifer Research Council, the Royal Society, ments published in several hundred Angell-James at the invitation of the British Heart Foundation, the Well­ research papers, he produced many Professor R Elsner to experiment on come Trust, the Special Trustees of St bricks building up a wall of knowledge, seals and to study the cardiovascular Bartholomew’s and St Mark’s Hospital helping us to understand the under­ and respiratory reflexes. Single nerve London, the Central Research Fund of lying mechanisms involved in cardio­ fibres from the receptors were also the University of London and the vascular and respiratory reflexes. The going to be studied. This necessitated National Institute of Health. During his studies involved anatomical and physi­ both physiologists taking apart their career he received prizes: the Schafer ological experiments in which he always respective laboratories and packing the Prize in Physiology, University College played a very active part. In many of equipment up and rebuilding it in a London 1953, the Thurston Medal the experiments it took him and an laboratory of the University of Alaska. Gonville & Caius College 1957 and the assistant, his technician Derek Bacon, The arrival of all the packets of equip­ Sir Lionel Whitby Medal Cambridge who was with him for 35 years, 12 hours ment caused not a little worry and University 1963. to prepare before any new information confusion at the customs at the airport In addition to all his research he could be obtained from the experi­ but was finally released and was able to contributed chapters in textbooks: ment. He was a magnificent surgeon continue its journey to the University. Lippold and Winton Human Physiology, and would silently work for many hours The Esquimox caught the seals which Starling Principles of Human Physiology painstaking dissections with magni­ were transported from the Bearing and Emslie-Smith Paterson Scratcherd fying glasses, often with instruments he Straights and there looked after by the and Read Textbook of Physiology. had designed himself to make the animal technicians who were experts at He was an active member of the surgery possible. There would be racks feeding them by hand with fish. The Physiological Society, frequently of Dale-Schuster pumps modified by same technicians were required to attending meetings and presenting him to produce a more natural pressure obtain giant frogs from the lakes to communications, posters or demonstra­ profile, mimicking that of the normal enable the nerve fibre recording equip­ tions and he served on its committee circulation, and tubes connecting ment to be tested. Once the experi­ and was made an honorary member in different circulations, allowing all the ments were finally started they lasted 1986. He was co-editor of The Journal of parameters of pressure, flow, tempera­ from 8 o’clock in the morning to 5 am Physiology from 1956-1963 and 1984­ ture, pH and chemical constituents to on the following day. However, 1989. He was a member of the Society be independently controlled. He had a although they were a huge test of of Experimental Biology and Chairman lathe in his office with which he was stamina, they were entirely successful of the Monograph of the Physiological able to make and modify his research and resulted in several publications Society 1981-1987. He was also a equipment. Subsequently he would concerning the diving response and the member of the European Underwater spend many hours accurately cardiovascular and respiratory sectors Biomedical Society from 1971. measuring all his results – a task he and their reflex responses in the seal. found it difficult to delegate. The accu­ These papers have recently been Family life racy of his measurements was made quoted in a book entitled Biology of In 1948 he married Beryl Esmé, possible by his careful calibration and Marine Animals edited by Jon Reynolds younger daughter of late Wing zeroing of all measuring equipment and Sentiel A Rommel 1999 in the Commander A J Nightingale, whom he before and after each experiment. In chapter Living in Water: Solutions of met when she was a nurse at Bart’s. truth he was a master following from Physiological Problems which was Family life was important to him and the traditions of other great cardiovas­ written by R Elsner, at whose invitation he had two sons and grandchildren to cular physiologists such as William the seal studies had been performed. carry on his genes. However, he worked Harvey, in whose footsteps he followed. He had many assistants and collabora­ so hard and such long hours that his He re-enacted William Harvey’s tors over the years, including Dr Mary family must have seen less of him than experiments when he made a film enti­ Scott (now Taylor), Dr Jennifer Angell- they would have wished. His compli­ tled William Harvey and the circulation of James, Professor Robert Elsner, cated experiments would sometimes the blood which received the Gold Professor Janice Marshall, Professor continue well into the small hours of Medal from the BMA in 1972. Michael Spyer, Dr Jane Ward, Dr John the night. He had a younger brother Travel was an important part of his Clarke and many more. who sadly died at the age of 33 in a OBITUARIES PN 41 helicopter crash in Malaysia. This had a Michael de Burgh Daly Prize Lecture profound effect on him and people who worked with him at the time said that his personality changed as a result, Many of you will know that Michael de Burgh Daly sadly died last year. leaving him a quieter and sadder man. Michael was not only a distinguished and respected scientist, he was a valued He tried to act as a surrogate father to colleague, enthusiastic teacher (to staff and students alike) and, most impor­ his brother’s children. He was a kind, gentle and very polite man with a shy tantly, a valued friend to many of us. and retiring personality who would Michael had a long association with the Physiological Society. He became a help anybody who asked for it. He was member in 1951 and was elected an Honorary Member in 1986. He served on in looks tall, slim with blue eyes, several of the Society’s Committees and Editorial Boards and in 1997 the commonly found in people of Irish descent. He was very careful about what Society published his seminal monograph on Peripheral Arterial Chemoreceptors. he ate, he never smoked and drank In memory of Michael’s association with the Society monies have been little alcohol. He always took exercise donated to the Society to fund an annual or biennial lecture in his name under in his younger days, playing tennis and enjoying walking. He loved to relax the auspices of the Cardiovascular/Respiratory Control and Autonomic Func­ with his family at Salcombe where he tion Special Interest Groups, the areas of research to which Michael attributed could walk and watch the boats. He enormously throughout his career. described himself as a model engineer The first Michael de Burgh Daly Prize Lecture, entitled Towards an under­ and his main hobby was designing, building and running hydroplanes. He standing of cardiovascular and respiratory integration was given by Professor Janice was a superb model engineer and Marshall (Birmingham University) at the UCL meeting of the Society in mechanic who made his engines with a December 2002. This was particularly apt since Michael’s first lecturing post in lathe from the solid blocks of metal. His class B hydroplane, Nipper 2, held 1948 was in the Physiology Department at UCL. Janice was an appropriate the European record of its class for choice to give the first Lecture not only because her own research has paral­ many years. At the time of his death he leled and built upon some of the important concepts that have arisen from was hoping to reclaim the record with another new model which he had Michael’s findings, but also because she knew Michael personally over a long designed and was building. He also period. Her Prize Lecture, to a packed Lecture Theatre, summarised some of sailed model boats which he had built. Michael’s elegant experimental approaches and the important conclusions he He remained physically and mentally reached regarding the importance of integration between cardiovascular and well until the last, despite having a heart attack in his 60s and more respiratory control. She then described how her own studies, firstly on periph­ recently some angina which was eral chemoreceptor reflex responses and the alerting/defence response followed treated with a coronary artery stent. later by studies on the response to acute and chronic whole body hypoxia were Michael de Burgh Daly contributed a huge amount to his subject of physi­ explained by and extended the concept of integrative responses. ology, both by his own research but In future years it is hoped that the Prize Lecture, in addition to allowing also by the influence he had on all established investigators to be invited to present to the Society, will provide an those who studied with him and under him. He was one of the last of the clas­ opportunity for younger researchers in this field to present their findings. sical experimental physiologists, a man If any of you would wish to contribute to the fund set up to endow the Prize who will be missed by family, Lecture and ensure its existence for many years to come, then please send colleagues and friends. cheques payable to the Physiological Society directly to the Treasurer, Professor Jennifer Angell-James JPT Ward at The Physiological Society, PO Box 11319, London WC1V 6YB. Please Great Missenden, Bucks mark any cheques and covering letters `Michael de Burgh Daly Prize Lecture’

David Jordan Department of Physiology Royal Free & University College Medical School 42 PN OBITUARIES

David Keynes Hill 1915 – 2002

using for his heat measurements the posts in operational research for the equipment that AV had developed at Army, finally becoming personal assis­ University College London. He re­ tant to Brigadier BFJ Schonland, scien­ examined the absorption of heat that tific adviser to Field Marshal Mont­ occurs during the first minute after a gomery. He was the first British scien­ contraction, and showed that it is tist to examine an unexploded V2 caused by the resynthesis of adenosine rocket, and he obtained information triphosphate (the immediate source of about ballistic missiles that would have the energy dissipated during contrac­ been launched by magnetic propulsion tion) by transphosphorylation from into Britain if the launching sites had phosphoryl creatine, and not by a stage not been overrun by Allied troops. in the formation of lactic acid from After the war, David returned to his carbohydrates as had previously been research on muscle, first at Cambridge, David Hill, physiologist and biophysi­ supposed. He also measured the time then (1948–49) as physiologist at the cist, died on 18 August, 2002. His courses of three other processes during laboratory of the Marine Biological father was AV Hill (known simply as recovery after a contraction that had Association in Plymouth, and finally as AV), a pioneer of biophysics who not been previously measured because biophysicist back in Hammersmith received a Nobel prize for his measure­ of their small size and slow time course: (vice-dean, 1970–76). Here his prime ments of the heat produced by muscles. oxygen consumption, production of duty was overseeing the development His mother was Margaret, sister of the heat and changes in pH. This was a of electronics and of instruments for economist Maynard Keynes, and of the remarkable achievement for a young observations on human patients, but surgeon and bibliophile Geoffrey scientist in so short a time and on the he had time to continue his research. Keynes who married a granddaughter strength of it David was elected to a Until 1971 he continued in the same of Charles Darwin. research fellowship at Trinity College. general field as his own and his father’s AV Hill is remembered chiefly for his On the outbreak of war, he started pre-war work, using physical tech­ mathematical formulations, both of the clinical study but soon joined a group niques on isolated muscles and nerves excitation of nerves by applied electric at the Postgraduate Medical School at but with an emphasis on the intracel­ current, and especially of the relations the Hammersmith Hospital in London. lular structure of muscle (neglected by between the force against which a Here he worked on the effects of crush AV) and using many original tech­ muscle contracts, the speed at which it injuries, which were expected to be niques. A group of his papers reported shortens, and the rates at which it among the most serious consequences optical changes in nerve and muscle. liberates energy as work and as heat. of air raids. AV Hill had led the team Another series of investigations on As a boy, David often acted as an developing anti-aircraft gunnery in the muscle used ultraviolet microscopy and assistant in his father’s experiments. First World War, and it was on his radioactive tracers both to localize the Like his father, he was an undergrad­ advice that in 1940 the physicist adenine nucleotides and phosphoryl uate at Trinity, Cambridge, which he Patrick Blackett was appointed as scien­ creatine in relation to the muscle-fibre entered in 1934 with a major scholar­ tific adviser to Anti-Aircraft Command. striations and to follow the intracel­ ship. In his first two years, he studied AV then provided him with three phys­ lular tubular system that communicates physics and chemistry as well as physi­ iologists as assistants, including his son with the external fluid. This system ology. He then registered as a medical David and myself. All of us had an serves to conduct the influence of exci­ student because in those days a medical adequate background in physics for our tation inwards from the surface qualification was a prerequisite for an work, which involved adapting the membrane of the muscle fibre to acti­ academic career in physiology. After gun-control equipment to operate with vate the contractile material. He discov­ doing the necessary anatomy and the the crude data provided by the radar ered a ‘short-range elastic component’ final-year physiology course, he had sets of that time, working on a wave­ in the response of resting muscle to one year of research before the length of three metres. This entailed stretch, which implied that a number outbreak of the Second World War. many visits to gunsites, both at practice of cross-bridges between the thick and In that year he continued his father’s firings and during air raids. thin filaments exist even in the resting work on isolated muscles from frogs, From 1942, David held various other state but are broken when the relative OBITUARIES PN 43

Professor Mary Pickford 1902 – 2002 displacement of the filaments When she arrived in England she was exceeds a few nanometres. Almost at first taught privately, sharing a all of his papers up to 1971 were governess with a cousin. In 1914 she under his authorship alone. was sent to Hamilton House, Tunbridge From 1971 until 1977, David Wells, and in 1916 to Wycombe Abbey collaborated with RHT Edwards and School. She enjoyed school and was his group in studies on human impressed by the person who taught muscle, measuring force, heat her the rudiments of playing the cello, production and chemical changes, but her school record was unremark­ the latter research requiring samples able. In 1921 she went to Bedford taken from their own muscles by College, London University, where she needle biopsy. From 1977, he read science, obtaining a first class continued his work on muscle with general honours in 1924. PA Merton, activating their own In 1925 she went to University College muscles by heroic procedures such © Godfrey Argent Studio, London London and began part-time work in as stimulating them with electric Mary Pickford started her career when pharmacology with the famous scien­ shocks through the skin and by there were few women doctors and tist AJ Clarke and then with EB Verney, strong magnetic fields applied to considerable prejudice against women with support from a Medical Research the brain. scientists; she went on to make her mark Council grant; she enjoyed working on In 1949, David had married on medicine and physiological science. the kidney and the heart-lung prepara­ Stella, sister of the immunologist She became determined when told by tion. While working part-time, she John Humphrey, and they had Sir Cooper Perry, superintendent of started clinical studies, this having three daughters. Following his Guy’s Hospital and later Principal of become practicable as her godmother retirement in 1982, David experi­ London University, that ‘women are no had left her an income of £120 a year. mented in photography, and, after good at that sort of thing’. Verney became ill and for a while he and his wife made their final Lilian Mary Pickford was born on 14 Pickford held the fort in the Pharma­ move to Yorkshire, he made himself August, 1902 in Jabalpure, in the centre cology Department, keeping one page extremely skilled in woodwork. He of India, where her father was a ahead of the students. She gained a died after a long illness in which he successful planter of indigo and ‘conjoint’ medical qualification in 1933 became progressively less mobile, tobacco. In the 17th century her fore­ and at University College Hospital met though he retained his faculties and bears had started the Pickford transport some of the great medical figures of remained cheerful until the end. service. Her father’s cousin, William that era – TR Elliot, Sir Thomas Lewis, I got to know David Hill well as Pickford, was Master of the Rolls, Wilfred Trotter and Sir Francis Walshe – an undergraduate: my own career created Baron Sterndale in 1918. His whilst amongst her contemporaries followed his closely from my arrival younger daughter, Mary Ada Pickford, were George (later Sir George) Pick­ at Trinity College one year after became one of the first women ering, and Harry (later Sir Harold) him. After he left Cambridge in members of Parliament. The Marquis of Himsworth, who became Secretary of 1948 we kept in touch until his Bristol was a great-grandfather. the Medical Research Council. The death. His friendship was of great At the age of six, Mary Pickford was medical school had only 60 entries importance to me, especially when left ‘at home’ in England with her aunt. annually and so, said Pickford, ‘One I first arrived at Trinity, younger The aunt’s husband was an engineer could know everyone and feel the than most of my contemporaries who specialized in work for hospitals, influence of great men. This was an and very shy. He was exceptionally especially for Guy’s. As a child Mary untold blessing and the place could be kind, gentle, modest and generous. was forever asking questions and her enjoyed.’ Is the present, politically He will be greatly missed. relations were tireless at finding appro­ driven, passion for numbers, rather priate responses. At first she wanted to than standards, not a retrogressive step’ Andrew Huxley be a doctor, later to do research; she After qualification Pickford under­ Grantchester, Cambridge ended up being both, a renowned took some junior hospital jobs but Reprinted by permission from Nature, 24 October 2002 medical teacher and research worker. Verney moved to Cambridge University 44 PN OBITUARIES

and she soon joined him there, from the mark. Much of Pickford’s questions. If a paper had been given by becoming a Beit Memorial Research work was concerned with the relation­ a young, nervous person or by Fellow. In 1939 she became a lecturer ship of two hormones, the anti-diuretic someone from abroad, the questions in the Physiology Department of Edin­ hormone that controls water balance were couched in the gentlest manner burgh University. During the Second by its action on the kidney, and and might contain helpful advice for World War, staffing levels were oxytocin that acts on the uterus. further studies. If, however, an experi­ minimal, and in some departments the She gained a DSc in 1951 in Edin­ enced person had blundered, and arrangements were wholly unsatisfac­ burgh and later was given an Honorary should have known better, she would tory. An Egyptian medical student with DSc by the Heriot-Watt University. In start the question in the most polite a wife and a number of children to 1954 she became a Fellow of the Royal manner but a few sentences later, using support, who repeatedly failed his clin­ Society of Edinburgh, in 1977 of the perhaps the phrase ‘you did not say… ical examinations, saw ‘a gap in the Royal College of Physicians of Edin­ did you?’, the flaw in the argument market’. He ran cram courses for the burgh, in 1966 of the Royal Society of would be exposed. students en masse, in the Odd Fellows London and in 1966 was the first Pickford made a number of lecture Hall, a stone’s throw away from the woman to hold a chair in the Edin­ tours in both North and South medical school; there they learnt, it burgh Medical Faculty. America. She had wit and a sense of fun. appears, by chanting strings of facts. She was always utterly straightfor­ She enjoyed being mistaken for her Mary Pickford kept the flag flying for ward in her dealings; this was alas not namesake, the star of the silent screen, physiology in this difficult period. She true of everyone in high places. She when checking into American hotels, also helped in outpatients at the Royal was especially concerned about the especially when this meant receiving Hospital for Sick Children. She spent welfare of the women students; at the bouquets of flowers or baskets of fruit. one Christmas in London during the end of a class in physiology she would This happened when she attended a Blitz, saw the city burning, did locums sometimes ask the women to stay Physiological in Boston Congress in for hard-pressed general practitioners behind after the men had left; she 1929; she had sailed across with other and inspected the vast underground would then give them some advice scientists on the liner Minnekahda. shelters. On returning to Edinburgh, on about, for instance, the advisability of After a day’s work in the lab she occasions she sang in the Usher Hall to learning ju-jitsu to protect themselves sometimes gave a dinner party in her entertain the troops. should the need arise. home. In 1951 she drove a 1933 Rover Pickford published extensively; her At one time there was a ‘Regency’ saloon car, the shock absorbers of work was endocrinological and related scheme for the students; as a regent which had become non-functional; she to the hypothalamus and pituitary. She Pickford would have had five students found that travel over the Edinburgh made observations on dogs; some allotted to her. She would invite them cobbles was more comfortable when needed substantial surgery, many only individually to her house for a sump­ the car was full of passengers. The trivial procedures. Some she trained to tuous tea and was interested in their increased mass would lower the reso­ urinate on command. The dogs lives; she was motherly and protective, nant frequency of the vehicle and tune enjoyed her company and she was very a very caring person. The regent system it away from the rhythmic percussive concerned with their welfare so that collapsed and now that the university drive from the impact of the seats. the observations would be as physio­ is swamped with numbers, this civi­ After she attended an evening class logical as possible. If, on some morn­ lized arrangement could not be revived. run by a most stimulating artist, ings, a dog was not taken up to the lab In 1963 and 1964 she attended the George Garson, in a cellar in the Royal the animal would bark to draw atten­ ‘Two Way Traffic in Ideas Seminars’ Mile, painting became an important tion to himself and to register his organised in Edinburgh by Tam Dalyell pastime for her. One year she went disappointment. On her door there was MP for Dick Crossman, then Shadow high up in the Andes and painted some sometimes the notice Go Away! Do Not Cabinet Secretary of State for Education of the indigenous people. She exhibited Even Knock. The knock would upset the and Science, and contributed in her annually with The Edinburgh Women dog and hormone levels would vary gentle and authoritative manner valu­ Artists, a group that she had started. In unpredictably. The picture so widely able and constructive ideas about retirement she went annually to a portrayed of terrified animals in medical education. At meetings of painting school in Mull and painted research could not have been further learned societies, she sometimes asked elephants from her childhood memo­ OBITUARIES PN 45

Laurence Malcolm 1913 – 2001 ries. She learnt about the techniques of his time at Mill Hill he published the silversmith, and about lapidary. many neurophysiological papers in In 1972 she moved for family reasons collaboration with Sydney Hilton, W to Derbyshire and worked three days a Feldberg and many others; his partic­ week at Nottingham University, where ular field was that of evoked poten­ she was appointed Special Professor of tials and their basis in spinal cord Endocrinology. She moved back to and brain. His mastery of experi­ Edinburgh in 1983 and was still driving mental technique was so precise that in her nineties. She joined the Senior it was an exquisite ‘art form’ to watch Fellows Club of the Royal College of and learn by. Physicians of Edinburgh (alias the ‘Old In 1959 Laurence Malcolm was Buffers’ Club’) and came to the awarded the Regius Chair in Physi­ lunches. Having trouble with both ology at Marischal College of the hips, she needed help from two people University of Aberdeen, where he to get up the steps into the building. introduced many innovative projects. She was for many years a member of Laurence Malcolm was the son of One was the intercalated science St John’s Episcopal Church in Princes Professor John Malcolm, who held degree for medical students, which Street, Edinburgh. The Right Rev the Chair in Physiology at the continues today as BSc Med Sci, based Neville Chamberlain, Bishop of University of Otago, New Zealand on his own experience in Otago. He Brechin, who was formerly the Rector from 1905 – 1943. He studied medi­ was also instrumental in building a of St John’s, in 1994 said of her: ‘To be cine at Otago from 1931, with a break well-respected BSc degree in physi­ in Mary’s presence is to step back in 1932 for a family sabbatical in ology, the first graduates coming in several generations and wallow in Britain, during which time he 1963, and incorporated in the final marvellous, intelligent conversation, attended classes at St Andrews and year an original research project – this savour the smells of India, learn the Edinburgh universities. After has given many students a ‘launch’ intricacies of animal physiology and completing his preclinical studies in into research careers over the years. marvel at the speed of technology in 1934, back at Otago, he took the In Aberdeen, Professor Malcolm the 20th century (she remembers opportunity to enter a science-based was concerned for the welfare and seeing the first man to fly in an aero­ course and achieved B Med Sci in enhancement of both staff and plane across the Channel!).’ 1935, probably a substantial contrib­ students. He believed that colleagues Mary Pickford never had television, utor to his interest in fundamental sharing their coffee break could also loved Turner’s paintings and enjoyed physiological research. Following his share ideas and solve problems in the music of Mozart, Beethoven and graduation with MB ChB in 1938, both teaching and research. His Britten. She wrote short poems and Laurence Malcolm completed his hospitality at parties at his home, whilst she never talked in the lab about house jobs in clinical medicine and House of Minmundy, was generous religion, she had theological discus­ then joined the Department of Physi­ and warm, providing for good rela­ sions with the rabbi who lived in the ology at Otago, where JC Eccles tions between staff and postgraduates other half of her house. arrived in 1944. in the department. In 1995 she moved south again, In 1944 Dr Malcolm came to work Professor Malcolm served as Dean needing by then to be in a nursing as an exchange lecturer at St of the science faculty at Aberdeen in home. Her health was fairly good Thomas’s Medical School and subse­ the early 1970s, and was instrumental until about three months before her quently was appointed as Reader in in developing more ‘modular’ course death, on her 100th birthday. She Physiology at St Mary’s Medical structures to increase the range of never married. School. After a year spent working possibilities for students. The founda­ with Professor Chandler Brooks in tion course in physiology was E Geoffrey Walsh New York, he was appointed to a post designed on the basis ‘What do we [email protected] working with Professor W Feldberg at expect them to know?’ for detailed Reprinted by permission from The Independent, the National Institute for Medical analytical study in more senior years. Obituaries, 23 August 2002 Research, Mill Hill in 1953. During During his time in Aberdeen 46 PN OBITUARIES

Stanislav Tuc˘ek 1932 – 2002

Professor Malcolm welcomed a daughter Lenka, in the loss of a variety of visitors from other coun­ charming, caring and courageous man. ries – particularly South America, Stefan Mellander from Sweden and Ann Silver Pavel Hnik from Czechoslovakia – The Physiological Laboratory to the neurophysiological laborato­ University of Cambridge ries. He supervised a number of research assistants and postgraduate students working particularly on Eberhard Buhl neurotransmitter actions as identi­ It is with deep regret that we announce fied from evoked potential studies. the untimely death of Professor Both staff and postgraduates were Eberhard Buhl. After a long period of encouraged to travel to conferences ill health his condition took a devas­ and to work in other laboratories. tating turn for the worse over the New In 1975 Professor Malcolm retired Year and he died of heart failure in the early, returning to his native New early hours of Saturday, 18 January Zealand, but settling in the north Many readers will be saddened to hear in the Leeds General Infirmary. island with plans to grow an that Stan Tu˘cek died in Prague on 27 Eberhard was a young man, but at 43 orchard of kiwi fruit. While his trees September, 2002. For the last three he had achieved more than many developed he worked at the new years of his life he had suffered uncom­ academics whose lives have not been University of Auckland in both plainingly from leukaemia. Although cut so tragically short. After gaining neurophysiological teaching and not a Member he was known to the medical qualification in Germany he research, publishing his last paper Society from his attendance as a enjoyed many fruitful years as a in 1980. Foreign Guest at UK meetings and as a neuroanatomist working in institutions Professor Malcolm maintained his co-organizer of our joint meeting with within Europe and as far afield interest in physiology to the end. the Czech Physiological Society in as Australia. He came to the UK to His keen intellect ensured his 1998. Recently he held a grant under work at the MRC Anatomical enjoyment of IUPS meetings in the Society’s Centres of Excellence Neuropharmacology Unit in Oxford. Glasgow, UK, Prague, Czech Support Scheme. He had a worldwide In 1999 he came to the University of Republic and, last of all, in reputation as a neurochemist and was Leeds to fill the chair in Neurobiology. Christchurch, New Zealand where involved in arranging and editing At Leeds he rapidly established one of he appeared delighted to meet old numerous important symposia on the the world’s leading neuronal network friends and full of life and energy, cholinergic nervous system. In the mid­ research groups and took over the reins despite celebrating his 88th 1960s he worked with Catherine Hebb as Head of the School of Biomedical birthday at the Congress. at Babraham, and later with S-C Cheng Sciences in January 2002. Laurence Malcolm had a wide in New York. His demise is an immense loss to the range of interests – including hill Despite the constraints on research University, his friends and colleagues walking and Rotary Club activities. in iron-curtain days, his laboratory in throughout the world and his family. He was actively involved as a lay the Institute of Physiology in Prague We extend our heartfelt condolences to preacher and vestry member in the was extremely productive as can be his wife Dora Lozsadi. Anglican church of New Zealand, seen from the bibliography in his 1978 working to form a New Zealand ‘sea monograph Acetylcholine Synthesis in The Neuronal Oscillations of faith’ group. Neurons. His productivity continued Research Group unabated to the end of his life: he was University of Leeds Ruth Payne still working on a paper during his final Old Aberdeen, Scotland spell in hospital. Friends throughout the world will A full obituary will be published in the next issue of want to extend their sympathy to his Physiology News widow Dana, his son Martin and his OBITUARIES PN 47

Reginald James Whitney 1914 – 2001

plethysmograph used for quantifying construction of a simulator which human peripheral blood flow. He estab­ imposed conditions of a ship’s pitch lished the technique over the next two and roll. When the Hampstead Unit years, exploring how, for example, was disbanded in 1974, he continued blood flow could be measured simulta­ this work at the RAF Institute of Avia­ neously in muscle and skin. His next tion Medicine, Farnborough and from major contribution at Oxford was the where he retired from the MRC in 1980. development and construction of a Reg’s wife, Joan, died in 1966 and he force analysis platform suitable for was then faced with the task of investigating whole body activities, bringing up his still young family impulsive actions, ballistocardiography alone. For the rest of his life his over­ and centre of mass, and studying a riding concern was for the happiness of wide range of subjects from world class his four children and six grandchildren athletes to his infant son. By the late in all of whom he took immense pride. 1950s it had become apparent that the During retirement at his home in Reg Whitney, outstanding for his force records required to be interpreted Barnes he continued to retain his inter­ research in biomechanics and human in association with photogrammetry ests and activity in biomechanics as physiology and distinguished as an and electromyography, and further, by well as indulging in his inherent inventor, died on 1 November 2001, the use of data logging and computer constructional skills. Reg was an affable aged 86. analysis techniques, the availability of and modest man with unique intellec­ Born at the beginning of WWI, he which at the time were hardly dreamt tual talents, and he will be remembered lived through difficult times during the of. In 1958, he moved from Oxford to with affection and admiration by all Depression and WWII, but he persisted the MRC Institute for Medical Research those who had the privilege of in his academic career in the 1930s, at Hampstead to set up a laboratory in knowing him. eventually obtaining a doctorate in human biomechanics where he zoology at the University of Birm­ continued to analyse human posture Ken Collins ingham. He had an addiction for devel­ and motion with applications in the Joe McGlade oping new methods and apparatus, Services, industry, sports and clinical which was put to good use in 1941 medicine. Whole-body activities such when he was directed into Army opera­ as in sports proved too difficult to tional research engaged in problems record adequately, but a more likely Emmeline Lesly Jervis arising for men operating tanks. Later, situation was presented by the Royal Elected 1960 his focus was in gunnery which he Navy with a request to investigate the began to develop as multi-disciplinary effects of ship motion on human Died 9 October, 2002 personnel research, an early link to performance. Thus he embarked on the ergonomics. As a senior scientific officer with the War Office his ideas and inter­ ests became more clearly defined in the The Journal of Physiology Symposia study of posture and motion during normal human activities, particularly Ion channels: their structure, function and control those of extreme activities such as at the joint annual scientific session of the Japanese Physiological and Pharmacological Societies lifting and handling heavy loads. Monday, 24 March 2003, Fukuoka, Japan In 1948 he joined the MRC Climate Organisers: Yoshihisa Kurachi and R Alan North and Working Efficiency Unit in Oxford. It was here, studying human muscle Speakers: Yoshinori Fujiyoshi John P Adelman action in the forearm, that he devel­ R Alan North Francisco Bezanilla Yoshihisa Kurachi oped the mercury-in-rubber strain Eric Gouaux Lily Yeh Jan Susumu Seino gauge which has become known world­ For further information go to: www.jphysiol.org wide as the Whitney strain gauge 48 PN BOOK REVIEW

New developments in hearing and balance Making sense of science Scientific Editors: Brian CJ Moore, – SuperCell Jonathan Ashmore & Mark Haggard Fran Balkwill and Mic Rolph British Medical Bulletin Volume 63, 2002 Portland Press, London. Oxford University Press. ISBN 0-19-851625-8. ISBN 1 85578 093 3. 247pp, £42.50 £6.99, paperback

When I was a student there were two recent trend towards increasing sub­ This book is the latest in the periodicals which I used to read, but specialisation and researchers focusing Making sense of science series from did not particularly like reading. on finer and finer molecular detail, this Portland Press Ltd. The books have These were Annual Reviews and the tendency is even more noticeable today been edited for children, teenagers British Medical Bulletin. I disliked Annual than it was 20 years ago. Providing an and families by prominent scien­ Reviews because they seemed to be all abstract, a brief introductory paragraph tists. The series editor is Fran turgid data and references, with hardly and a brief conclusion does not, in my Balkwill and the series illustrator is any pictures and little or no attempt opinion, suffice. Mic Rolph. To date the books to provide perspective. The British I was amused to note that an attempt have all been well received and Medical Bulletin also struck me as a to engage the ‘Medical’ in British have sold very well. pictureless wasteland of facts, but with Medical Bulletin has been made by For reasons that I find hard to the added disadvantage that it was including a brief ‘Key points for clinical fathom SuperCell does not gel as printed in a font size of about 4, so that practice’ section in some of the chapters. well as others in the series. It you needed a magnifying glass simply However, when key points are deemed attempts to cover a wide readership, to read it, let alone figure out what it to include ‘There is now little doubt but fails to do it as well as the rest was going on about. that cochlear structure allows the inner of the series. This is unfortunate Twenty years later, Annual Reviews ear to perform like a multichannel since the book is very well still seem exactly the same as far as I can mechanical spectrum analyser’, I doubt produced, as would be expected tell. However, I have both some good that the volume is likely to be taken off from Portland Press, and is profusely news and some bad news regarding the the shelf in many clinics. and colourfully illustrated. British Medical Bulletin, as judged from Lest anyone thinks that I am being Early on the concept of cells (and this present volume. First the good too negative, I should at this point state that we are all made up of cells) is news. The size 4 font has now been that I do find this current volume of introduced, but it is not done well. banished from the text and replaced the British Medical Bulletin, as previous Many different cell types are shown with one that, even now, I can read volumes which I have consulted in the as early as page 4, but no idea of comfortably without mechanical aid. past, to be a useful compendium of their likely functions is shown and Not quite such good news, however, is information. The editors have done a an idea of their size does not appear that – as if in deference to a venerable good job in marshalling a wide variety until page 15. In addition there are tradition – the mini font has been of contributions which do indeed sudden jumps in both the style and retained for tables, figure legends and survey new developments in hearing level of approach, as when intro­ references, so I was not able to dispense and balance. I am sure many researchers ducing the concepts of the plasma with my magnifying glass altogether. in the field will find individual contri­ membrane, ribosomes, the Golgi Now for the bad news. There are still butions helpful and informative. But I system, cytoskeleton, mitochondria hardly any illustrations, resulting in can’t help feeling that review and chromosomes in just two page after page of densely referenced compendia such as these end up being pages, albeit facing pages! text. I am sure this will delight card­ quoted more than read. In today’s For me this particular book does carrying afficionados of the field, but wired world, where finding scattered not work well, but the rest of the the disadvantage is that anyone else is information is easier than ever before, series is very good and Balkwill and likely to suffer rapid and strong seda­ the purpose of reviews which are mere Rolph are to be praised for the tion. Personally, I still find the relative compendia of facts, rather than overall concept. Hopefully, further lack of serious attempts to provide a creative digestions, becomes a more books in the series will be as good wider context for the contributions prominent question than ever. as the previous ones. both surprising and fundamentally inexcusable. If anything, with the John A Lee Bill Winlow The Benevolent Fund of the Physiological Society PO Box 11319, London WC1V 6YB Telephone 020 7269 5713 Fax 020 7269 5720 DONATION FORM

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PHYSIOLOGICAL SOCIETY SOCIETY FOR NEUROLOGY FOR Noticeboard SCIENTIFIC MEETINGS EXPERIMENTAL BIOLOGY NEUROSCIENTISTS IV No notice is carried for more (For further details, please visit ANNUAL MEETING Magdalen College, Oxford than three successive editions. Notices are starred so that http://www.physoc.org/Meetings/future.html) Forty years of invertebrate 7 – 8 April, 2003 readers can see at a glance 2003 neuropharmacology – a tribute to The Guarantors of Brain have kindly whether this is the first (one Professor Robert Walker Newcastle upon Tyne – 3-4 April agreed to sponsor a ninth symposium star) or final (three stars) Dublin – 8-10 July Southampton on Neurology for Neuroscientists. appearance of the notice. The aim of this symposium is to provide Manchester – 10-12 September April, 2003 Notices for the Summer 2003 Cambridge – 17-19 December neuroscientists with the clinical Further details from: edition of Physiology News background to neurological diseases, and 2004 should reach the Publications Professor Roddy Williamson with insights into how neurological Office by 12 March, 2003. Glasgow – March Email: [email protected] problems can illuminate basic Babraham Institute, Cambridge – May neuroscience. Further details, including a * Cardiff – July full programme listing and application Please note that while members Cork – September forms are available from: are welcome to advertise King’s College, London – 20-22 December 40th SPRING MEETING www.ion.ucl.ac.uk/neurochemistry/N4N/ relevant events in Physiology 2005 OF THE BRITISH index.html News and on the Society’s website, advertisements via Bristol – July MICROCIRCULATION * SOCIETY email will be restricted to events sponsored by the Society. University of Bristol BRITISH NEUROSCIENCE The Benevolent Fund of the 7 – 8 April, 2003 ASSOCIATION ANNUAL Physiological Society The meeting includes a symposium on MEETING NOTICE OF ANNUAL Lymphatic Research Harrogate GENERAL MEETING UK Organiser: Dr Dave Bates 13 – 16 April, 2003 The Trustees hereby give notice that the Further details from: Details from: Annual General Meeting of the BMS Secretary Dr Richard Ribchester Benevolent Fund will be held at 1 p.m in Microvascular Research Laboratories Email: [email protected] the Eisai Lounge, University College Department of Physiology * London on Tuesday, 8 April 2003. University of Bristol Jo Hancock Southwell Street 22ndALTERNATIVE Benevolent Fund Administrator, Bristol BS2 8EJ for and on behalf of the Committee Tel 0117 928 9818 MUSCLE CLUB Tel: 020 7269 5713 Fax 0117 928 8151 University of Leeds Email: [email protected] Email: [email protected] 15 – 17 April, 2003 www.microcirculation.org.uk The Alternative Muscle Club is an Abstract and registration deadline informal meeting organised by young YOUNG PHYSIOLOGISTS’ 7 March 2003 scientists for young scientists and is now SYMPOSIA 2003 ** in its 22nd year after the organisers hand over the torch of responsibility to a Prospective bids to hold symposia new institution every year. The AMC is a in 2003 should in the first instance 7th ANNUAL special meeting that encourages young be forwarded to Maggie Leggett at MOLECULAR research students, postgrads, postdocs [email protected]. TECHNIQUES and those with an interest in muscle WORKSHOP biology to participate and develop University of Coventry communication skills as well as meet University College, Cork May/June 2003 other scientists working in the field. The 7 – 16 April, 2003 event will feature guest speakers at the Whole body human physiology A 10-day residential workshop, cutting edge of muscle research. Main contact: sponsored by the Physiological Society Such a unique blend of fun and science Douglas Thake ([email protected]) and the Wellcome Trust, for the training in such a relaxed atmosphere is a great of physiologists in molecular biological advertisement for muscle biology and techniques. The course is appropriate for the scientific world itself and should not BENCH TO BEDSIDE physiologists who are reading for a PhD be missed. SYMPOSIA or are at the post-doctoral level and who The cost of the event for the three days is ION CHANNEL DISEASE have little or no previous experience of £100 (includes accommodation, molecular techniques. The course will be entertainment and all meals including Royal Society of Medicine, London limited to 16 students, who intend to the legendary AMC Conference Dinner). follow a career in the physiological 28 March, 2003 Email: [email protected] sciences. Preliminary enquiries to: Further details from: www.leeds.ac.uk/bms/amc2003 Dr Maggie Leggett Royal Society of Medicine * The Physiological Society 1 Wimpole Street, London W1G 0AE Tel: 020 7290 2965 PO Box 11319 Fax: 020 7290 2977 London WC1V 6YB Email: [email protected] Email: [email protected] * * Noticeboard entries continue on page 52 52 PN NOTICEBOARD

BIOCHEMICAL SOCIETY INTERNATIONAL SOCIETY techniques applied to single cells. It is workshop. There is no need to apply intended for postgraduate students, post directly to the Dale and Rushton funds FOCUSED MEETING ON FOR AUTONOMIC doctoral workers or established scientists before workshop applications are CALCIUM OSCILLATIONS NEUROSCIENCE (ISAN) wishing to apply these techniques in assessed. their research. and5th UK MEETING ON Calgary, Alberta, Canada Bursaries – The workshop can provide CALCIUM SIGNALLING 4 – 8 July, 2003 • The following basic techniques are some half bursaries – if you think you will offered: two electrode voltage clamp, have difficulty funding the full fee please University of Liverpool Special features of this meeting will patch clamp, single electrode voltage indicate in your application. include a relatively inexpensive 1 – 2 May, 2003 clamp, dye injection, ion-sensitive Paper and email copies of the application registration fee (about Canadian $550) microelectrodes, fluorescent indicators. Calcium is a ubiquitous second should be sent to: and reduced registration fees for messenger involved in variety of • There are 16 places. Participants David Ogden postdoctoral fellows and students. The physiological functions. work in pairs and have the opportunity Microelectrode Techniques fee will cover the cost of the meeting to do three 3-day experiments in the two Day one of this two-day meeting is NIMR banquet and some meals. Economical weeks. In addition, lectures and practical a Biochemical Society focused meeting The Ridgeway accommodation is also available. There sessions on electronics, data acquisition on calcium oscillations honouring the London NW7 1AA, UK will be opportunities for junior faculty and computer analysis and microscopy retirement of Professor Cobbold Email: dogden@nimr/mrc.ac.uk members to present major lectures in will be given. Daily lectures given by (University of Liverpool). addition to posters. teachers and visiting lecturers cover the Information on internet: Day two is the 5th UK meeting on Calcium www.fp.ucalgary.ca/isan2003/ basic techniques taught and specialised www.nimr.mrc.ac.uk/events/microelectrode.h Signalling where more general aspects of topics. A copy of the Plymouth Micro­ tm calcium regulation will be discussed. electrode Handbook will be provided. ISAN Satellite Symposia * Speakers • Accommodation (for 14 nights – Day 1 ENTERIC arrive and depart on Wednesday) is close THE CONGRESS OF Sir Michael Berridge Babraham, UK NEUROSCIENCE to the laboratory and includes breakfast. THE LATIN-AMERICAN Peter Cobbold Liverpool, UK Lunch is provided in the department Anne Green Warwick, UK Banff, Alberta, Canada each day and an allowance given for an ASSOCIATION OF Richard Lewis Stanford, USA 9 – 13 July, 2003 evening meal. PHYSIOLOGICAL Ole Petersen Liverpool, UK Trevor Shuttleworth Rochester, USA Email: [email protected] • The course fee of £1100 includes SOCIETIES (ALACF) Alec Simpson Liverpool, UK www.med.ucalgary.ca/webs/ENS/ accommodation, meals and tuition. AND BRAZILIAN Andy Thomas UMDNJ, USA Participants are responsible for their own David Yule Rochester, USA PHYSIOLOGICAL travel arrangements. SOCIETY (SBFIS) Day 2 AUTONOMIC The closing date for applications is 30 Martin Bootman Babraham, UK April 2003. A meeting to assess Ribeirao Preto, State of Sao Paulo, John Carroll UCL, UK DYSFUNCTION AFTER applications will occur during May and Dermot Cooper Cambridge, UK Brazil SPINAL CORD INJURY: all applicants will be notified of the Tomoko Kamishima Liverpool, UK 1 – 4 September, 2003 John McCarron Glasgow, UK MECHANISMS, outcome. * Steve O’Neill Manchester, UK PREVENTION AND How to apply Steve Pennington Liverpool, UK There is no application form. Please note Rosario Rizzuto Ferrara, Italy TREATMENT IUPS 2005 – that printed and emailed copies are Alexei Tepikin Liverpool, UK Banff, Alberta, Canada required. 35th CONGRESS OF THE * 10 – 11 July, 2003 1 Please give a concise description of INTERNATIONAL UNION SECOND WORLD Email: [email protected] your research, your reasons for wishing OF PHYSIOLOGICAL CONGRESS ON [email protected] to attend and your experience of SCIENCES www.isanweb.org/meetings/ techniques taught on the workshop. List FETAL ORIGINS OF satellite2003a.html in order of priority four techniques you San Diego, CA, USA would like to learn. ADULT DISEASE * 31 March – 5 April, 2005 Brighton Centre, UK 2 Provide a brief CV (2 sides IUPS 2005 is being organised by the six 7 – 10 June, 2003 SIXTH IBRO WORLD maximum) and list of publications. member societies of the US National Committee of the IUPS, the American www.foad2003.org/ CONGRESS OF 3 The application must be Physiological Society, the Society for * accompanied by a letter of NEUROSCIENCE recommendation from an academic Neuroscience, the Microcirculatory 3rdCONGRESS OF THE Prague, Czech Republic referee, preferably PhD supervisor or Society, the Society of General 10 – 15 July, 2003 Head of Laboratory. This letter should Physiologists, the Biomedical Engineering FEDERATION OF indicate how your career, the laboratory Society and the Society for Integrative * EUROPEAN PHYSIO- in which you work and the area of and Comparative Biology, under the LOGICAL SOCIETIES research you intend to pursue will benefit auspices of the US National Academy of MICROELECTRODE from your participation in the workshop. Sciences. Nice, France TECHNIQUES FOR CELL www.IUPS2005.org/ 28 June – 3 July, 2003 4 What is your likely source of funding? PHYSIOLOGY Funding * Further details from: FEPS2003, CNRS UMR 6548 20th Workshop 3-17 September 2003 Applicants with MRC or BBSRC University of Nice – Sophia Laboratory of Marine Biology studentships – simply state you have a Antipolis, Faculté des Sciences Association of the UK, Citadel Hill, studentship in your application. Do not 06108 Nice Cedex 2, France apply to the Research Council directly. Plymouth PL1 2PB Tel 33 4 92 07 68 51 Dale and Rushton funds of the Fax 33 4 92 07 68 50 Information for applicants: Physiological Society – help is usually Email: [email protected] • The workshop provides intensive available for young scientists working in www.unice.fr/FEPS2003/ practical experience of a number of the UK. If you wish to apply please * microelectrode, patch clamp and optical indicate in your application to the