PHYSIOLOGY NEWS
winter 2010 I number 78
A celebration of JZ Young Heart size and Prometheus’ giblets Is industrial experience useful? New initiatives for undergraduate physiologists New technology for physiology courses saves time, money and resources! Free up your lab for more sessions.
ADInstruments has announced that LabTutor 4 with Our technology provides the opportunity to Server and Online components will be released on reduce lab session times without changing the March 1, 2010. This technology provides remarkable quality of learning, time and cost savings through: double student numbers without Remote student access to experiments doubling data Pre-lab preparation or post-lab data analysis acquisition systems and reporting, outside the lab. and eliminate printed Independent learning lab materials. Self-contained experiments that include background, objectives and instructions, real data acquisition, analysis and reports, all in one adinstruments.com/labtutor4preview easy-to-use interface. Centralised administration Follow this address to find out Single-point control for any number of courses, more and register for your preview. lab sessions, and networked locations.
EQUIPMENT CERTIFIED FOR HUMAN CONNECTION
UK • GERMANY • USA • BRAZIL • CHILE • INDIA • JAPAN • CHINA • MALAYSIA • NEW ZEALAND • AUSTRALIA
LabTutor4PhysiologyAd280x200.indd 1 25/1/10 12:10:49 PM PHYSIOLOGY NEWS Editorial 3 The Society’s dog. ‘Rudolf Magnus Meetings gave me to Charles Sherrington, who Towards an understanding of the enteroendocrine system 4 gave me to Henry Dale, who gave Sensory processing: from transduction to behaviour me to The Physiological Society in Frank Sengpiel, Richard Apps, Bridget Lumb 5 October 1942’ An introductory workshop on human and clinical physiological techniques Stuart Goodall, Angela Atalla, Mary Morrell 6 Published quarterly by The Physiological Society Techniques Contributions and queries Hierarchical clustering of multidimensional data Senior Production Editor Patricia de Winter 8 Jill Berriman Letter from America Editorial Administrator To study motion, how closely must you live with it? Maev Fitzpatrick Joanna Offord 12 The Physiological Society Publications Office Science News and Views PO Box 502, Cambridge CB1 0AL, UK Leptin receptor regulation – links to obesity? Lynda Williams, Tel: +44 (0)1223 400180 Ruben Nogueiras 14 Fax: +44 (0)1223 246858 Does activity in the lateral cerebellum reflect predictive Email: [email protected] control of visually guided movements? Nadia Cerminara 16 Website: www.physoc.org Prometheus’ giblets Buel Rodgers 19 Magazine Editorial Board Bloodless revolution Caroline Pond 21 Editor Exercise-induced lipid mobilization in humans: the role of Austin Elliott catecholamines revisited Max Lafontan, Vladimir Stich 24 University of Manchester, Manchester, UK Work against gravity: in search of the molecular switch for Members mechano-regulated muscle plasticity Martin Flück 28 Angus Brown Noticeboard 30 University of Nottingham, Nottingham, UK Letters to the Editor 30 Patricia de Winter Memorable physiologists University College London, London, UK John Zachary Young – invitation to the dance Fabio DeSio, Sarah Hall Andrew Packard 32 Cardiff University, Cardiff, UK From the archives Austin Elliott 35 Unbelievable! 36 Munir Hussain University of Bradford, Bradford, UK Society of Biology Mark Downs 37 Society John Lee Should The Physiological Society accredit university courses? Rotherham General Hospital, Rotherham, UK Mike Collis 38 Thelma Lovick Reports University of Birmingham, Birmingham, UK Royal Society Seminar – Science collaboration in a multi-polar Samantha Passey world Liz Bell 39 Bristol Heart Institute, Bristol, UK Royal Society Policy Lab – The future in your brain Liz Bell 40 Foreign Correspondents Gareth Roberts Science Council Lecture Liz Bell 40 John Hanrahan Science for Humanity McGill University, Montreal, Canada Thailand water project: using scientific knowledge to alleviate John Morley poverty Anu Devi, C Uy 42 University of Western Sydney, NSW, Australia Ask a physiologist! 43 Education Fiona Randall Okinawa Institute of Science and Technology, Okinawa, Physiology core curriculum Richard Dyball 44 Japan In vivo pharmacology and physiology techniques: acting to © 2010 The Physiological Society increase awareness and understanding Richard Apps 45 ISSN 1476-7996 (Print) A year in industry Laura Corns 46 ISSN 2041-6512 (Online) Cardiff University Physiological Society Stuart Hanmer, James Selvey 47 The Physiological Society is registered in England as a company limited by guarantee: No 323575. The resounding success of a new undergraduate initiative Registered office: PO Box 11319, London WC1X WQ. Ania Szmuksta 48 Registered Charity: No 211585. Exercise physiology sixth form workshop Jayne Hastings 49 Printed by The Lavenham Press Ltd Young Physiologists’ Symposium Steve Thomson 50 Affiliate news Industrial experience – a stepping-stone on the pathway to career success? Sam Passey 51 The Society’s journals Experimental Physiology 52 The Journal of Physiology 54 New Council Member 55 Obituaries
Cover image: The original drawing of the John Spence Gillespie Ian McGrath 56 Advancing the science of life rabbit in Life of Mammals by JZ Young, p.34. PHYSIOLOGY NEWS Action points Guidelines for contributors In this issue Grants These guidelines are intended to assist Welcome to the first Physiology News The Society offers funding through authors in writing their contributions of a new decade. the following grant schemes: and to reduce the subsequent editing process. The Editorial Board of Physiology Looking over the News and Views Travel Grants, Non-Society News tries to ensure that all articles are articles, there seems to be something Symposia Grants, Outreach Grants, written in a journalistic style so that they of a ‘back to basics’ theme going International Teaching and Research will have an immediate interest value for a on, with articles concerning either Grants and the Vacation Studentship wide readership and will be readable and moving, or eating or growing. I am and Departmental Seminar comprehensible to non-experts. Scientific hoping that next time we will have articles should give a good overview of Schemes. For full information, some reproduction and some sleeping a field rather than focus entirely on the please visit: to complete the set. www.physoc.org/grants authors’ own research. Format of articles On a historical theme, we feature two Membership applications The main message or question posed of the most singular figures of 20th Applications for membership to The should be introduced in the first century biology, both better known Physiological Society are considered paragraph. The background for the topic by their initials than their names. on a rolling basis, and a decision is should then be established, leading up to They are JZ Young, remembered by normally made within 15 working the final conclusion. Fabio DeSio and Andrew Packard on days. For full information, please Length of articles p. 32, and AV Hill, who described the visit: This will be determined by the subject famous Hill equation in The Journal of www.physoc.org/membership matter and agreed with the Senior Physiology 100 years ago (p. 35). Production Editor. Is your membership information This issue also see a slight re-launch Submission of articles of our Education section. It is a correct? Authors should submit articles as a Word Please check and update your truism (or at least something often document attached to an email. mentioned by ageing scientists, details at www.physoc.org, under Illustrations should be sent as separate including editors) that scientific ‘My Physoc Profile’. attachments (see below) and not embedded in the text. disciplines rise or fall by how well they manage to get young people Illustrations and authors’ photographs interested, and keep them interested, Physiology News Authors are encouraged to submit in pursuing education, training and Deadlines diagrams, drawings, photographs or other artwork with their articles and a research in the subject. To that end Letters and articles and all other photograph of the author(s) should we have a range of features looking at contributions for inclusion in the accompany submissions. llustrations physiology education in universities Summer 2010 issue, No. 79, should and photographs may be colour or black and (pp. 44–50), including how to form reach the Publications Office white, and preferably TIFF, JPEG, PDF or AI a student physiology society (p. 47). ([email protected]) by 22 April files with a minimum resolution of 300 dpi. We also have a new feature, Ask 2010. Short news items and letters References a Physiologist (p. 43), where sixth are encouraged, and can usually be Authors are requested to keep the form students can pose questions for included as late number of references to a minimum – answering by Members (volunteers to copy if space permits. preferably no more than two or three. answer questions welcome!). Please cite all references in The Journal Suggestions for articles of Physiology style (see Information and I like to think that JZ and AV would have approved. Suggestions for future articles are Guidance for Authors: http://jp.physoc.org). welcome. Please contact either the Editorial Administrator or a member of the Editorial Board of Physiology News (see contents page for details). Physiology News online www.physoc.org
The Physiological Society permits the single copying of individual articles for private study or research. For permission to copy or reproduce for any other purpose contact [email protected]. Opinions expressed in articles and letters submitted by, or commissioned from, Members, Affiliates or outside bodies are not necessarily those of The Physiological Society. EDITORIAL PN 3
Science, engineering and the general election Making sure that science and Evan Harris MP, on January 13th. key challenges facing science and engineering are seen as election They were asked questions on a engineering in the UK. issues has been the focus of our range of topics including: funding, recent work at the Campaign for impact and the ring fence; support As we continue to move science and Science & Engineering (CaSE). It for industry and research charities; engineering up the political agenda, might be thought that such areas and education. it will give the politicians concerned should be apolitical – logic and about science and engineering a rational analysis should lead you The debate provided a great stronger case to fight for improved forward. But in reality, science is opportunity for the audience to see policies and funding. And the more rarely so decisive and even when it is, what discriminated the speakers and that the electorate show that they the government needs to implement for the speakers to hear and feel the care, the more forceful that case policies that fit into our political, audience’s concerns. Please find a becomes. financial and ethical world. summary and links to the webcast on the CaSE website and blog. It Our blog, CaSE Notes, details the In fact, CaSE works mostly on policies is well worth a watch, not just for different parties’ commitments that affect science, engineering and its political content. It was a lively and links to many other resources. related subjects, campaigning to evening chaired by Roger Highfield, Sign-up to our e-bulletin and follow improve how they are taught, how Editor of New Scientist, with many us on twitter to keep up to date. The research is funded, how government entertaining, and some decidedly Physiological Society is a member draws upon expert advice, and how it unexpected, moments. of CaSE, but we would be delighted organises their place in government. All clearly political issues.
It is vital that science and engineering policies are clearly spelled out in manifestos for the electorate before they vote. There are over 3 million graduates in science, engineering and related subjects in the workforce who will want to know that their concerns are taken seriously. And It is worth appreciating the interest to welcome you as an individual the general public is becoming which the event provoked. Despite member too. more and more interested in these the snow that day, 350 people turned subjects. It is impossible to ignore out, with a further 140 watching live There is also much that you their importance in shaping the online and hundreds of comments can do directly. Write to your UK’s responses to both national on twitter. Within a week, the debate local prospective parliamentary challenges, like rebalancing the was viewed on the web 1300 times. candidates, in fact, write or economy, and global ones, like The point is that people care. Science comment on the issues wherever climate change. and engineering policies matter to you can, from blogs to letters to the people far outside Whitehall. local or national press. You could Over the last six months or so, ask questions about science and we have been working with It is only to be expected that the engineering on radio or television our members, including The science spokesmen will discuss programmes, or at your local Physiological Society, and other science policy, but we want to hear hustings, or even organise your own, collaborators, sharing information commitments from the party leaders if necessary. and pooling resources. CaSE has too. The Prime Minister was the Politicians have been asked to been meeting with politicians and first to give a speech on science in prioritise science and engineering in their advisors to discuss a range of February 2009. He was followed, their policy-making, please play your issues that we hope will be covered just a few weeks ago, by the Liberal part in encouraging and supporting in the election manifestos. Democrat leader, Nick Clegg. David Cameron has yet to make a major them to do this. As part of this work, CaSE organised speech on science, although he a science and engineering policy has mentioned it and its role in Hilary Leevers debate between Lord Drayson, re-balancing the economy. We are Campaign for Science & Engineering Minister for Science and Innovation, very keen to hear a dedicated speech his Conservative Shadow, Adam from him. CaSE will also be writing www.sciencecampaign.org.uk Afriyie MP, and the Liberal to the party leaders asking them http://blog.sciencecampaign.org.uk Democrats’ Science Spokesman, Dr how their party will respond to the http://twitter.com/sciencecampaign
Physiology News | No. 78 | Spring 2010 | www.physoc.org 4 PN MEETINGS
Towards an understanding of the enteroendocrine system Metabolism and Endocrinology Themed Meeting, AstraZeneca, 24–26 March
Invited Symposium Speakers
Carlos Diéguez University of Santiago de Compostela, Spain Josep Vidal Hospital Clinic Universitari, Barcelona, Spain Soraya Shirazi-Beechey University of Liverpool, UK
An increasing amount of information total of thirteen invited speakers. In Jens Holst is appearing on the role of the addition there will be oral and poster Panum Institute, Copenhagen, incretin effect in the modulation of communications. The symposium Denmark many biological mechanisms such will aim to provide a broad spectrum Rachel Batterham as food intake, insulin secretion, of knowledge on the gut endocrine University College London, UK metabolism and even cardiovascular system from both a cellular and a actions. It is very timely to try whole-organism approach so should John McLaughlin and bring together scientists have a wide appeal. By the end Hope Hospital, Manchester, UK in this exciting area to review of the meeting we would expect Graham Dockray developments. attendees to have been exposed to University of Liverpool, UK a thorough discussion of the role Bariatric surgery, such as Roux-en-Y of the enteroendocrine system and Pat Brubaker gastric bypass, has shown that there how it integrates nutrient handling. University of Toronto, Canada are rapid beneficial effects upon type 2 diabetes often before the The meeting will be held in the Steve Bloom weight loss effects have been seen. recently opened Conference Centre Imperial College, London, UK The rapidity of response strongly of AstraZeneca Pharmaceuticals at Fiona Gribble suggests a gut endocrine effect. It Alderley Park, Cheshire. Alderley University of Cambridge, UK is already known that the incretin Park, which is set in 400 acres effect during a glucose challenge of parkland 14 miles south of Frank Sundler or meal time is blunted in type 2 Manchester, has been the site of University of Lund, Sweden diabetes and can be enhanced by pharmaceutical research since 1957 gastric bypass surgery. The two main and has seen the development Rémy Burcelin incretins, glucagon-like peptide-1 of novel drugs, particularly in the INSERM, Toulouse, France (GLP-1) and gastric inhibitory peptide cardiovascular and oncology areas. Peter Flatt (GIP), are secreted by endocrine cells University of Ulster, UK of the intestine in response to food Late registration deadline 10 March and have a wide range of powerful 2010. systemic effects. GLP-1 therapies are being utilised in the treatment of type 2 diabetes and obesity Physiology News questionnaire with the development of stable GLP-1 analogues. The gut mucosa Tell us your views on Physiology News and win an Acer netbook also contains cells responsible for secretion of other hormones such We are keen to hear what you think of Physiology News – too much of as ghrelin, peptide YY (PYY) and something, not enough of another? Fill in our short survey and one cholecystokinin (CCK), which can lucky respondent will receive an electronic notebook – if you want to be also influence energy balance. There entered for the draw please make sure you include your email address or may be many more novel ones still membership number. to be discovered. http://www.surveymonkey.com/s/magsurvey The symposium will take place over five half-day themed sessions with a
Physiology News | No. 78 | Spring 2010 | www.physoc.org MEETINGS PN 5
Sensory processing: from Institute of Ophthalmology), on pitch of questions they had not dared to discrimination and sound localisation ask earlier in the day. The roving mic transduction to behaviour in the auditory cortex (Andrew King, proved essential for these sessions, – the first Cellular & University of Oxford), on understanding which revealed a previously unknown pain and pain relief through brain talent of Maria Fitzgerald (UCL) as she Integrative Neuroscience imaging (Irene Tracey, University of metamorphosed into Graham Norton. Themed Meeting at Oxford) and on the cortical processing These were followed by posters and of olfactory and taste stimuli (Edmund trade exhibitions. In a close contest Cardiff University Rolls, Oxford Centre for Computational between many high-quality entries, The Society’s Blue Riband poster The Physiological Society held its first Neuroscience). In the afternoon, competition was won by Annette Allen Cellular & Integrative Neuroscience we moved on to central control of (University of Manchester), followed by Themed Meeting at Cardiff University sensory processing; we heard talks on feedforward and feedback processes Michael Bale (University of Manchester) from 14–16 December 2009. and Laura Cornelissen (UCL). BCNC The meeting featured a focused in visual grouping (Pieter Roelfsema, Netherlands Institute for Neuroscience, awarded a similar prize for the best symposium on ‘Sensory processing: oral communication by an early from transduction to behaviour’ with The Netherlands) and on descending control of spinal nociception career scientist, and this was shared an excellent line-up of 18 invited between Timothy Brown (University of speakers from the UK and abroad. (Bridget Lumb, University of Bristol). Regrettably, Mathew Diamond (SISSA, Manchester) and Stephanie Koch (UCL) The programme also included 20 – it would be great if a similar incentive oral communications and 44 poster Trieste, Italy) was unable to deliver his talk since he had his wallet stolen upon could be provided by The Physiological presentations. The meeting was Society at future Themed Meetings. organised by the Bristol Cardiff his arrival in Britain and had to return Neuroscience Collaboration (BCNC), home. The Society Dinner was held at represented by Frank Sengpiel (Cardiff Aberdare Hall, one of the first university University), Richard Apps and Bridget halls of residence for women built in Lumb (both University of Bristol). Britain. Entertainment was provided not only by band Capital Groove The meeting attracted 147 registered but also by Prem Kumar in his role participants as well as five exhibitors as stand-up comedian aka Meetings whose sponsorship is much Secretary. The meeting organisers appreciated. The meeting consisted thanked Sarah Barnsley and Nick of five half-day sessions, each of them Boross-Toby from The Physiological dealing with sensory processing at Society for all their hard work that a different level, from the sensory contributed to making this meeting a organs to behavioural output, and very successful one. Thanks were also between them covering all five due to Vanessa Davies and Catherine senses. We kicked off with a session Hortop from the Cardiff Neurosciences on sensory transduction, including Centre and Anne Cooke from Bristol talks on mechanoreceptor neurons in Neuroscience for their help with the skin (Gary Lewin, Max Delbrück preparing the meeting. Center, Berlin), outer hair cells in the cochlea (Helen Kennedy, University of The conference finished with a theme Bristol), rod and cone photoreceptors business meeting which provided an (Hugh Matthews, University of The last day was dedicated to motor opportunity to alert Society Members Cambridge) and sensory neurons in integration and behaviour. Again, we to the deadlines for proposals for the mammalian olfactory epithelium heard fascinating presentations on symposia at the 2011 Main Meeting (Hiroaki Matsunami, Duke University, a wide variety of subjects, including as well as for the next Cellular & USA). In the afternoon of day one, vomeronasal influences on behaviour Integrative Neuroscience Themed three talks on subcortical processing (Peter Brennan, University of Bristol), Meeting, also to be held in 2011. covered a wide range of topics, from action-based sensory coding in Participants were reminded that the the development of brainstem pain spinal sensorimotor modules (Jens Themed Meetings are open to all control systems (Maria Fitzgerald, UCL) Schouenberg, Lund University, Society Members with an interest in the respective theme, regardless of the to thalamocortical interactions in the Sweden), the contribution of single perhaps narrower focus of invited talks processing of visual information (Adam somatosensory cortex neurons on a particular topic. Please contact Sillito, UCL Institute of Ophthalmology) to behaviour (Michael Brecht, the Theme Leader, Frank Sengpiel and the coding of sound localisation in Bernstein Center for Computational ([email protected]), with your ideas the auditory midbrain (David McAlpine, Neuroscience, Berlin) and feedforward for proposals – the success of Cellular and feedback learning in human UCL Ear Institute). & Integrative Neuroscience as a theme sensorimotor control (David Franklin, depends on the active participation of The morning of day two was University of Cambridge). dedicated to cortical processing, and all members! this included talks on the dynamics The first two days were concluded by of population activity in the visual lively round-table discussions in which Frank Sengpiel, Richard Apps cortex (Matteo Carandini, UCL participants were able to ask all sorts and Bridget Lumb
Physiology News | No. 78 | Spring 2010 | www.physoc.org 6 PN MEETINGS
An introductory workshop on human and clinical physiological techniques King’s College and Imperial College London, 10 and 11 December 2009 From a PhD student’s perspective: respiratory loop gain to a group of Stuart Goodall, Final year PhD international physiologists?’. student, Brunel University Our department was sent into a flurry of excitement at the prospect of hosting and organising a day of physiology workshops in December, as part of The Physiological Society’s two-day International Workshop. Brainstorming and planning started in earnest back in the autumn and no member of the team was left out; workshops on non-invasive ventilation, chemosensitivity, EEG and London was chosen to be the venue transcranial Doppler occupied our for the first UK-based International waking hours as we prepared to play Workshop on human and clinical hosts to a varied mix of physiologists physiological techniques. The from all over the world. two-day workshop at the beginning of December 2009 was held at King’s As the week approached protocols College London and Imperial College were perfected, multiple choice questions concocted, and nerves ran London. small groups and they were hands-on, amok. The more I prepared for my which provided a thorough learning The workshop began with a series lecture on loop gain, the more the experience. After lunch another series of lectures. Firstly, an insight into subject became an enigma to me and of informative lectures followed. techniques used in human physiology all chances of an erudite presentation was given followed by the human The workshop allowed me to meet seemed to slide away. body response to high altitude. After students from all over the world Daunted? We were. Apprehensive? brief refreshments, an intriguing and enhance my knowledge of Most certainly. Ready to rise to the lecture detailing acceleration physiological techniques. I am very challenge? Absolutely and completely. physiology was presented and the appreciative of The Physiological response to cold water immersion Society for allowing the workshop The last few days saw an followed. After lunch, delegates were to take place and also this year’s unprecedented level of activity in given the opportunity to attend two organisers, Steve Harridge and Mary the labs and what was a veritable of four practical sessions, covering Morrell, who provided a thoroughly blitzkrieg spirit as the team pushed a variety of applied techniques enjoyable programme. on to put the finishing touches to assessing human function. Practicals four workshops and various lectures. were led by experts in the relevant From a research fellow’s perspective: The work done we enjoyed meeting field; the small-group design Dr Angela Atalla, Imperial College, the attendees at an evening session provided a thorough understanding London where posters of previous work of the topic and we were free to ask they had done were exhibited. As questions at any time. To finish off post-graduates, it’s not often enough the day, delegates were invited to that we stray from the relative participate in a poster session which comfort of our own area of research served as a tremendous opportunity so it was an unusual treat to be able for us to network and discuss to hear about such varied research research. topics from an enthusiastic group of people from such a wide variety of The second day began with a choice backgrounds. of two practicals from four, all emphasising techniques that are used Our day of hosting the workshop in a clinical setting. Mary Morrell and There are some words every research at Imperial College was a great her research fellows ran practicals fellow shudders to hear from their experience for us all; we all learnt a covering the areas of cerebral blood advisor. To the more conventional list, lot about organising and hosting a flow, EEG, application of non-invasive which includes enquiries about power large group, as we interacted with ventilation and measurement calculations and ethics applications, the attendees about our subjects. of chemosensitivity. As with the I would suggest the addition of Perhaps the highlight for me was the practicals on day one, we were in ‘Would you like to give a lecture on final session given by two previous
Physiology News | No. 78 | Spring 2010 | www.physoc.org MEETINGS PN 7
PhD students who, having completed their PhDs in years gone by, came Microelectrode techniques for cell physiology back to tantalise us with tales of their successes since graduating. An The Marine Biological encouragement to us all. I was also Association, Plymouth, UK gratified to hear that my lecture had gone down well and that people had 8–22 September 2010 understood my research area. 27th workshop From an organiser’s perspective. Dr Mary Morrell, Imperial College, A variety of marine and other preparations will be used to illustrate the London possibilities and limitations of these techniques. The workshop is intended mainly for postgraduate students and postdoc workers from any discipline who wish to learn techniques for use in their research.
Closing date for receipt of applications 30 April 2010
Application details from: www.mba.ac.uk/microelectrodecourse.php [email protected]
You simply cannot organise an Physiology in International Workshop without a great bunch of colleagues and Simulation 2010 the outstanding support of The Physiological Society staff. I was definitely blessed in this respect – Bristol, UK everyone did a great job in producing a series of top-class sessions for the Hi-Fidelity Simulation Applied to the Biomedical Sciences workshop, and the delegates did a great job in navigating their way Physiology in Simulation 2010 is a workshop-based symposium aimed at across London from one campus to presentation and discussion of developments in high-fidelity manikin-based another, despite our directions! simulation. The emphasis of the meeting is the application of physiological modelling to basic biomedical science and medical education. We had been briefed that the delegates wanted hands-on experience, and this became our Workshop & programme details to follow shortly priority in organising the two days. The aim of the second day was to illustrate how different physiological techniques can be applied to research questions in a clinical context. This 22/23 March 2010, aim reflects my observations that communication between specialists University of Bristol can help to facilitate breakthroughs in clinical physiology, although it is a challenge to maintain the cross- theme communication if time is Organising committee- Dr Richard Helyer & Prof Judy Harris, limited. The workshop was successful AIMS Centre for Excellence in Teaching & Learning, University of Bristol. in that it attracted participants For further information contact- [email protected] +44 (0) 117 3311459 from many different countries and backgrounds. Indeed, it was both stimulating and encouraging to meet so many enthusiastic people from across the world. So as last cords of Auld Lang Syne fade away maybe we Physiology in Simulation 2010 is organised, hosted and sponsored by the can look forward to a bright future Applied and Integrated Medical Sciences (AIMS) Centre for Excellence in for physiology in the new decade. Teaching & Learning, University of Bristol, Bristol, UK
Physiology News | No. 78 | Spring 2010 | www.physoc.org 8 PN TECHNIQUES
Hierarchical clustering of multidimensional data In the previous two articles of this clusters the ion channel genes based series, we looked at how to go about on their expression pattern across finding which targets within a set the samples, so for example, panel B of microarray data are statistically genes are highly expressed in atria significant, taking into account (mostly bright red), exhibit lower the problem of multiple testing. Patricia de Winter expression in the ventricles (mostly At this point, we should therefore bright green) and moderately be armed with a list of significantly expressed in Purkinje fibres (black, different genes, proteins, single the heatmap clusters samples into dark red and dark green). In this nucleotide polymorphisms (SNP), groups based on similarity of their analysis, the right and left atrial or whichever other entity was the ion channel gene expression: there samples are indistinguishable from target (measured variable) of the are two major groups, or branches each another and similarly, left and array. For specialised applications of the tree, one for atrial samples, right ventricular samples do not that investigate a particular process, and the other for ventricular cluster separately. Deuteranopic for example a microarray for and Purkinje fibre samples. The males will experience some difficulty cardiovascular-related genes, this rightmost branch subdivides into with this red–green visualisation so I list may not be too daunting, but two, separating ventricular samples will use an orange–blue gradient for in many cases arrays generate a list from Purkinje fibre samples. The tree heatmaps in the remainder of this that can easily run into hundreds of on the left-hand side of the heatmap article. targets, particularly when they are genome-wide studies for expression, DNA methylation or SNP. A lengthy enumeration of targets does not immediately reveal patterns in the data that can be visually summarised at a glance. This is in effect what PF PF PF PF LA LV RV LV RV LV LV LV LA LA RA RA RA LA RA RA LA PF PF PF PF LA RV RV RV LV LV RV RV LA hierarchical clustering can achieve. RA
Hierarchical clustering has become a popular way to summarise multidimensional data for a number of reasons: large data sets are readily simplified, groups of CIC2 CIC7 either targets or samples can be Kv4.3 identified on the basis of similarity CIC6 KChAP and the data are presented in InsP3R1 Nav1.7 A the style of a phylogenetic tree, CALM1 such as that used by taxonomists. Kvβ3 TASK2 Additionally, hierarchical tree KvLQT1 MIRP1 diagrams or dendrograms are HCN3 often combined with a heatmap, a matrix which allows individual values to be represented on a Cx40 colour gradient, commonly from HCN4 bright red through to bright green Navβ1 TASK1 via black, with grey representing TWIK1 Kv1.5 non-expressed or missing values Cavα2δ2 B (Fig. 1). In this figure, reproduced Kv1.6 Kir3.1 from The Journal of Physiology, each Cav3.1 HCN1 square represents the expression Cav1.3 value in one sample for a given Kv1.3 MIRP3 gene. In this figure, hierarchical clustering has been performed CASQ2 KChIP2 C on 32 samples from human heart SERCA2 and Purkinje fibres and also on 79 Na/K ATPase α3 ion channel genes so the matrix contains 32 x 79 squares (Gaborit FigureFigure 1 1. Example of hierarchical clustering of gene expression data. Reproduced et al. 2007). The dendrogram above from Gaborit et al. (2007), with authors’ consent. See text for explanation.
Physiology News | No. 78 | Spring 2010 | www.physoc.org TECHNIQUES PN 9
Table 1. Illustrative data set derived from Gaborit et al. (2007). Samples are: LA, left without affecting the information, atrium; LV, left ventricle; RA, right atrium; RV, right ventricle; mean (±S.D.), n = 7. that is the dendrogram exhibits isomorphism and can be drawn in many ways. The length of the branches is proportional to the distance of one profile to another: profile here is defined as either a data column (sample profile) or a data row (gene profile). Distance is a measure of similarity between profiles and can be calculated in a number of ways, the commonest of which are Euclidean, Manhattan and correlation. Euclidean and Manhattan are geometric measures of distance that in two-dimensional space can be plotted using Cartesian co-ordinates (Fig. 2A). The Euclidean distance, d, between the two points, A) B) d Equationa and1A b, dcana,b be obtained a1-b1 by usinga2-b2 4 2 2 b Pythagoras’ theorem (eqn (1A)): c 2 . 2 ( ) = ( ) +( ) 3 √(4 + 3 ) = 5. The Manhattann (also e 2 known as city block) distance for Equation 1B. d P,Q p1-q1 this point would bei the sum of the b 2 1 dotted lines,( or) = 7. Euclidean( ) and a Manhattan distances =1 n generally 1 2 3 4 a produce similar clusters, but Equation 1C. d P,Q p1-q1 from the Manhattani distance the Figure 2. A, Euclidean and Manhattan distances plotted on Cartesian co-ordinates. The Euclidean distance of two points a and b (blue and orange circles) is represented effect of large values or outliers is ( ) = =1 | | by a continuous green line and can be calculated using Pythagoras’ theorem. The lessened as the calculation does Manhattan distance is represented by the dotted lines. B, Pythagoras’ theorem can not include a squared term. We will 2 2 2 2 2 be extended to any number of dimensions, here a + b + c + d = e . look at Euclidean distance in a little more detail. Pythagoras’ theorem In this article, to simplify four random sets of data that have a can be extended from triangles explanations and the somewhat mean and standard deviation similar to any shape (Fig. 2B), or indeed large dataset, I will omit the to that of the original (Table 1). anything that can be represented Purkinje fibre samples and use a by numbers in order to calculate Distance measures small selection of ion channel genes Euclidean distances between sets from Gaborit et al.’s paper. I have We will now examine the of data. For microarray data, the selected 13 ion channel genes from dendrogram in more detail. The Euclidean distance, d, between two the supplemental information file nodes (intersection of horizontal sets of numbers P and Q, in this and for each gene have generated and vertical lines) can be rotated case two profiles, can be given by
Figure 3. Eucidean and Manhattan distances applied to multidimensional data. The Euclidean distance between two profiles, in this case an atrial and a ventricular sample (LA1 and LV7, respectively), can be calculated using eqn (2B). The vertical dashed red lines represent the difference in expression for each gene on the
abscissa, or p1 – q1, which are then squared and summed. The square root of this value is the Euclidean distance. The Manhattan distance is
simply the sum of the differences p1 – q1.
Physiology News | No. 78 | Spring 2010 | www.physoc.org 10 PN TECHNIQUES
smaller the value of r, the greater expression is lost during the ranking the distance between profiles, to a process. It is worth noting that maximum distance of 1. A negative correlation in this context is not value for r means that two profiles being used to test a null hypothesis are inversely correlated; for example, of no correlation between groups downregulation of one gene is of samples or genes; hierarchical accompanied by upregulation of clustering is not an inferential another. For a perfectly negative statistical method. correlation r = –1 and the two profiles will also have a distance of Making profiles comparable zero between them – the negative Prior to applying a measure of value of r is squared prior to distance it is common to adjust the subtracting from 1, so that distance data to make profiles comparable. I Figure 4. Scattergram illustrating remains a value between 0 and 1. deliberately avoid the use of specific correlation – perfectly positively A well-known disadvantage of terms here because every book, correlated variables (blue circles), Pearson’s correlation method is that software manual or web page I have perfectly negatively correlated variables it is very sensitive to outliers: a single read uses the same term for different (green squares) and uncorrelated data point can produce a correlation mathematical procedures. Before variables (orange triangles). Pearson’s where there is none, and outliers are adjusting your data, it is essential to correlation coefficient = 1, –1 and –0.14, not uncommon in microarray data. read the manual for the data analysis respectively. For this reason, it is more common software you are using to determine Pythagoras’ theorem (eqn (1A)) to use Spearman’s correlation for how a particular procedure will applied to multidimensional data microarray data. In Spearman’s affect it. The commonest procedure (eqn (1B)). If the squared term correlation, the data are replaced is to subtract the mean value of is removed from eqn (1B), and by ranks, which greatly reduce the a profile from each observation effect of outliers. One disadvantage in that profile, and then to divide the term p1 – q1 is bracketed by a modulus (absolute values) this gives of Spearman’s correlation is that the profile standard deviation into the Manhattan distance (eqn (1C)). the direction of change in gene each calculated difference. The Although Euclidean distance for such data cannot be represented directly on a graph, I have attempted a visual representation using a pair of sample profiles recreated from Gaborit et al.’s data (Fig. 3). These data are in fact profiles generated from quantitative PCR rather than hybridisation to microarrays, but the data are analysed in the same way. In this example I have compared two sample profiles, but as with any of these measures of distance, the same analysis can be applied to gene profiles. A disadvantage of these geometric measures of distance is that they are not scale invariant; two profiles that exhibit a similar pattern of expression, but vary greatly in magnitude, will appear very distant.
Correlation is a measure of distance that is computed by a statistical test. If two identical profiles are plotted, all the data points will fall on a straight line with no scatter, and if the data are subjected to Figure 5. The profiles of two left atrium samples are plotted without adjusting the a correlation analysis, Pearson’s data (A) and after rescaling so that the mean of each profile is equal to zero with a correlation coefficient, r, will be standard deviation of 1 (B). Note that in B, the dotted red lines p1 – q1 are shorter unity (Fig. 4). The distance, d, overall (for clarity, only the longest two are shown in each graph) so both Euclidean between these profiles is computed and Manhattan distances decrease. The pattern of expression remains similar as 1 – r and is therefore zero. The following adjustment.
Physiology News | No. 78 | Spring 2010 | www.physoc.org TECHNIQUES PN 11
A) B)
C) D)
Figure 6. Unsupervised hierarchical clustering of randomly generated datasets derived from Gaborit et al. (2007). Group
means ± S.D. are reported in Table 1. Spearman’s correlation (A and B) or Euclidean distance (C and D) were performed on unadjusted data (A and C) or following adjustment so that profiles have a mean of zero and standard deviation of 1 (B and D). For the sample dendrogram (clustering of column data), right atrial samples consistently cluster into one group, irrespective of the method used. Clustering of left atrial and ventricular samples exhibits dependence upon the method; however, with the exception of sample LV6, correlation is able to distinguish atrial and ventricular samples. For the gene dendrogram (clustering of row data), clustering exhibits strong dependence upon the method. mean of this new data set will be all possible pairs of profiles are microarray data, the commonest zero with a standard deviation of compared with each other to find the method is average linkage. The 1. This procedure standardises the pair that has the smallest difference mean of each pair of observations data to z-scores and is applied to all between them. This would be (measurements) for the two most profiles. The effect of this procedure laborious by hand but is computed in similar profiles is calculated to on geometric distances of profile milliseconds by clustering software. produce a new ‘average’ profile, and data is illustrated in Fig. 5. For When both row and column data the distances between this cluster geometric distances, this overcomes are subjected to clustering this is and all other profiles is recalculated the problem of sensitivity to scale, known as unsupervised hierarchical to find the profile or profile pair discussed above. For Pearson’s clustering. If, for example, we nearest to the averaged profile. The correlation where the samples are wish to cluster genes but keep the process is repeated until the tree is not a time series, this simplifies the samples in some order that we complete. As profiles and clusters are calculation of r and is recommended; impose, such as treatment groups, added, the tree’s branches lengthen however, when the data are a time the clustering is supervised. The because the distances become series, the direction of change in samples in Fig. 1 were clustered larger. An alternative linkage method gene expression may be lost. using correlation and the two that that is also used for microarray data were most closely correlated were is complete linkage. Rather than Linkage methods – building the RAIII and LAIII, so this cluster pair averaging profiles, the observations dendrogram has the shortest branches. In order in the first cluster (that with smallest In order to compute distances to find the distance between a distance value) are compared with between profiles for clustering cluster and remaining profiles, a those in all the other profiles to and start building a dendrogram, method called linkage is used. For find the two observations that have
Physiology News | No. 78 | Spring 2010 | www.physoc.org 12 PN TECHNIQUES/LETTER FROM AMERICA the largest difference between Letter from America – To study motion, how them. Only the profile in the first cluster that contains one of the two closely must you live with it? observations is used to recalculate the distances between the remaining Having bookended extensive time unclustered profiles to find the ‘on the road’ with studies into next nearest profile or cluster, and human movement, I have mirrored so forth. The opposite of this is to my work in the lab with a life filled use the smallest rather than largest with motion. Travel has long been observed differences and is called described as a function for a state single linkage, but as this tends to of peace and knowledge, but just as produce an effect called ‘chaining’, Kurtz in Conrad’s Heart of Darkness is where the tree lacks fine detail, it is driven mad by the environment and not usually used for microarray data. his distance from ‘home’, how would I fare with movement research, while Complete linkage generally produces on the road? compact, well-defined clusters and My best friend, Bonnie, and I (left) works well where there are strong Over the past two years, I have had enjoying the ambient static electricity patterns in the data. It does not on top of a Guatemalan volcano. Two the pleasure of roaming through minutes later lightning struck! perform as well when the data are India, living in Australia, climbing noisy, as microarray data often are. volcanoes in Guatemala, sun baking By the time I had finished writing Average linkage is an intermediate in Mexico, snorkelling in Belize up my thesis and presenting it in between single and complete linkage and finally living in New York. I November of 2008, my feet were and tends to perform well with began my journey studying and itching. During the year my interest microarray data. writing my Honours thesis on the in studying medicine had grown but neurophysiology of movement, and the year-long application process The reliability of hierarchical ended it working in motor control looked, well, long. I had left for India clustering by 1st December. Watching snake at Columbia University in New York. charmers and intricate Indian dances It should now be evident that the To my knowledge, I have escaped fed my interest in neuromotor choice of distance measure and Kurtz’s fate and my movements and research, while days suffering with linkage method can have a profound travels have clarified my ideas and bouts of ‘Delhi belly’ fuelled my effect on the outcome of hierarchical thoughts on my studies. clustering. This is illustrated by desire to go to medical school. By the the differences between the four After my degree in my hometown time I returned to Australia, I sent in dendrograms in Fig. 6. The reliability of Sydney, Australia, I was lucky to my application and decided to spend of hierarchical clustering can be take an optional year of research the year living in New York City with my best friend to stretch myself both assessed objectively. A permuation at the Prince of Wales Medical professionally and academically. Or test can be applied to determine Research Institute, supervised by at least that’s what I told my parents. whether the clustering differs from Richard Fitzpatrick. This meant my With friends, we diverted through that which would occur by chance previously purely academic studies Central America for 2 months. alone. I gave a detailed explanation were supplemented with ‘home of permutation tests in the first mechanics’ forays into welding, In perhaps the only instance of a article of this series and thus it wood construction, circuit design, Canadian citizen flattering the USA, will not be repeated here [2]. The beginner’s programming and How Sir Francis Head wrote, ‘the heavens advantage of this method is that it To Use Bicycle Parts To Create A of America appear infinitely higher returns an exact probability and is Terrifying Apparatus 101. I became – the sky is bluer – the air is fresher – free from subjectivity. very good at diverting the attention the cold is intenser – the moon looks of subjects from the steel-, cog- and larger – the stars are brighter – ...’ He In the next article of this series, bolt-ridden planks upon which I goes on. This was when the USA was principal component analysis will be conducted my experiments. To study described as ‘the new world’, and explored. our perception of ground height as needless to say, things have changed. My first contact with the States was Patricia de Winter we walk, I measured healthy subjects’ limits of height detection between in the suburbs of Anaheim, California, References their feet – their height threshold where not much can be described as ‘fresh’ except for the layer of paint Gaborit N, Le Bouter S, Szuts V, Varro A, – by making them stand or walk Escande D, Nattel S & Demolombe S (2007). over increasingly smaller changes in on the Disneyland rides, and plenty Regional and tissue specific transcript height. The year was an intense one of things are ‘large’, but the moon signatures of ion channel genes in the non- would be the last thing on my list. diseased human heart. J Physiol 582, 675–693. but I enjoyed it and moved along a very steep learning curve about de Winter P (2009). Physiology News 76, On arriving in New York, I was eager 24–27. physiology research. to investigate the American style of
Physiology News | No. 78 | Spring 2010 | www.physoc.org LETTER FROM AMERICA PN 13 research and took an opportunity to Measurement of gene meet and work with Pietro Mazzoni, co-director, with John Krakauer, expression using real-time of the Motor Performance Lab in quantitative PCR the Department of Neurology at 29–30 March 2010, King’s College Columbia University, in uptown London Manhattan. The experience of moving to a new city, finding a place The Physiological Society is to live, learning my way around and sponsoring a 2-day ‘hands-on’ trying to avoid being run over was an workshop to learn the principles overwhelming one. I expected to be of qPCR, focusing on the practical similarly out of my depth when I met steps required to design, set-up, with Pietro and the lab at Columbia. validate and analyse real-time qPCR I was, but in a different sense. The assays. research being done at the Motor Performance Lab was incredible – it A fellow researcher, Sophie Ryan, Enquiries and registration: demonstrating the motor study setup at had the uncommon combination [email protected] of being both clinically applicable Columbia University. and theoretically profound. As a (the first was the 2009 Australian Course organised by David Sugden 22-year-old from Australia, fresh Neuroscience Society conference at and Patricia de Winter out of my Bachelors degree, there which I presented a poster) so to say were many ‘little fish, big pond’ it was the largest is not a powerful moments. Despite this, learning statement. Nonetheless, nearly about the lab made me feel much 31 000 neuroscientists descending more comfortable than many of on the Chicago convention centre is the other cultural lessons I had quite a sight! been discovering. Science research is arguably the most international As I write this in my final days at the of professions; pushing back the Motor Performance Lab, I am excited boundaries of knowledge requires to return home and start medical sharing results and ideas. There school, but am also filled with a sense Meetings accommodation of unfinished business. It seems that was constancy to equipment, the Student accommodation has techniques and the attitudes that the more experiments you do, the improved immeasurably in the made me feel a comfort that I’m more you discover you need to find 50-odd years since I started sure many other researchers have out. I have spent the past two years attending Society Meetings. I have found in a lab in a foreign city. moving through parallel experiences: memories of some very peculiar My work at Columbia University treading across several countries with rooms, some so peculiar that it is centred on a trade-off that exists in only a growing list of all the other best not to identify any of them. the motor system between speed places I must explore, and roaming There was the high building in a and accuracy, called Fitts’ Law. around the realm of the neuromotor This describes a robust inverse system asking more questions than I gale-prone city that swayed so logarithmic relationship between could ever have answered. much it gave a nautical quality to the speed of a movement and its ones sleep. In another residential necessary accuracy. Of particular block, the lifts served every other interest was how submovements – floor – specifically the floors that the hypothesized simple components didn’t have bathrooms. A particular of gross movement – optimized the challenge was mounted by the speed–accuracy trade-off. safety-minded university where overloading of electric circuits Meanwhile, life in New York started was prevented by a trip switch in to feel more natural. I travelled the corridor outside each room. back to Australia for my medical Brain coral in the Caribbean. People arriving in the evening school interview and had the usual gloom could just about read the traveller’s realisation that nothing As Saint Augustine was reputed to notice explaining how to reset the much seems to have changed when have said, solvitur ambulando (it is trip. Later arrivals went to bed in you return. A highlight of the latter solved by walking). I hope to keep the dark and grumped all through part of the year was attending the travelling and return to physiology breakfast. Society for Neuroscience Chicago research soon, and with more ideas. conference. It was only the second Ann Silver conference I had ever attended Joanna Offord
Physiology News | No. 78 | Spring 2010 | www.physoc.org 14 PN NEWS AND VIEWS
Leptin receptor regulation – links to obesity? Obesity is characterised by high circulating levels of leptin, a hormone that limits the amount of body fat. This paradox has led to the concept of leptin insensitivity in obesity. We investigated the regulation of leptin receptor gene expression and protein number in response to leptin and diet to see whether receptor regulation could play a role in the development of leptin insensitivity
Leptin was first discovered when the as they are present on the choroid obesity seen in the ob/ob mutant plexus and on the brain microvessels. mouse was identified as being due to a single gene mutation resulting We set out to look more closely at in the complete lack of the hormone the regulation of leptin receptors leptin. Similar mutations, although in the brain, in particular the short very rare, have been found in forms on the choroid plexus and the Lynda Williams and Ruben Nogueiras humans, with leptin replacement long form on hypothalamic neurons, reversing obesity, emphasising the of specific receptors. Five isoforms to find out more about how gene role of leptin in the maintenance of a of the leptin receptor have been expression and/or receptor number lean body mass. identified to date; Ob-R(a–e). were changed by circulating levels However, only the long form of of leptin, diet and nutritional status Leptin is mainly produced by fat. the receptor, Ob-Rb, is capable of (Mitchell et al. 2009). We used in situ Leptin can act as a long-term eliciting a full signalling response. hybridisation for gene expression signal to the brain that adequate The short forms of the receptor, studies and in vitro autoradiography energy is stored, and can also act Ob-Ra and Ob-Rc, are thought to act to visualise labelling the receptor as a short-term signal, with levels as leptin transporters into the brain with the ligand [125I]leptin. These are dropping during fasting. Leptin receptors are present in many Figure 1 tissues. The key site of action for A Ob-R leptin is in the brain, particularly the ‘energy balance centres’ in the hypothalamus. Normally, Choroid Plexus leptin signals the hypothalamus to inhibit feeding and increase energy expenditure, thereby maintaining ‘normal body weight’. However, ARC high levels of circulating leptin, B Ob-Rb which occur in obesity, fail to stop overconsumption, leading to the concept that in obesity the loss of potency of leptin is due to leptin ‘insensitivity’. A number of different mechanisms have been proposed ARC to account for the development of leptin insensitivity. It has been C SOCS3 suggested that leptin receptor signalling may be impaired, for example, by high levels of suppressor of cytokine signalling 3 (SOCS3), an inhibitor of leptin signalling via the Janus kinase 2 (JAK2)/ ARC signal transducer and activator of [125I]leptin binding transcription 3 (STAT3) JAK/STAT D pathway. Signalling is terminated in part by the induction of SOCS3 Choroid Plexus production. The induction of SOCS3 gene expression can be used as a marker of induction of the JAK/STAT pathway. Figure 1. A, the distribution of leptin receptor gene expression. Ob-R – all forms of The potency of hormones is the receptor and B, Ob-Rb – the long signalling form of the receptor. C, SOCS3 gene regulated in part via the presence expression and D, [125I]leptin binding in sections of mouse brain.
Physiology News | No. 78 | Spring 2010 | www.physoc.org NEWS AND VIEWS PN 15 ideal techniques for looking at gene the effect of leptin on the regulation through the cell via the receptor is expression and receptor number in of receptor gene expression or inhibited by high-fat feeding, which complex tissues such as the brain as number. leads to an increase in the number of the signal over each anatomically receptors trapped at the cell surface. distinct area can be quantified A drop in the level of circulating separately (Fig. 1A–D). We wanted leptin, seen in fasting, gives rise to Another mechanism by which to know what factors regulate increases in both receptor number obesity may cause leptin insensitivity leptin receptor gene expression and receptor gene expression in is the inhibition of the up-regulation and number, and whether receptor all regions of the brain measured. of the expression of the long regulation could play a role in the The fasting-induced drop in leptin signalling form of the receptor by development of leptin insensitivity. appeared to be important for leptin (Fig. 3A). The up-regulation the subsequent down-regulation of the receptor by leptin was We looked at receptor gene of gene expression and receptor unexpected as some reports have expression and receptor number in number in response to increased foundFigure that 3 a down-regulation of the brain of the C57Bl/6 mouse by leptin levels seen on refeeding. This the receptor occurs in obesity manipulating the level of leptin by was emphasised by the fact that but other studies have found no fasting, which drops leptin levels, increasing the levels of circulating A refeeding, which raises leptin leptin by both a high-fat diet and by ARC levels back to normal, and feeding injecting leptin had more complex a high-fat diet, which raises leptin effects on gene expression and 200 ** levels in response to increased receptor number depending on the *** adiposity. We also injected leptin to region of the brain examined and on 150 further raise levels, in normal mice whether the long or short forms of and those on a high-fat diet, to see the receptor were measured. 100 if a high-fat diet would interact with We were able to identify two 50 (% of control) potential mechanisms by which Figure 2 Choroid Plexus obesity may induce leptin Ob-Rb gene expression 0 Control Leptin Leptin A ** insensitivity via receptor regulation. 1 hr 1 week *** The first was the down-regulation ** Low-fat *** of receptor number by high levels 120 of circulating leptin (Fig. 2A). Data ** High-fat 110 from studies in cells transfected with Low-fat High-fat 100 a green fluorescent protein (GFP)- tagged leptin receptor from our lab 90 Low-fat High-fat 80 and others (Belouzard et al. 2004)
I]leptin binding shows that the endocytosis of the 70 ARC
125 receptor into the cell is constitutive B 60 (% of control) and that leptin has no influence over *** 250 50 the rate of uptake into the cell. This *** Control Leptin Leptin Specific [ Specific 1 hr 1 week indicates that down-regulation of *** 200 ** Low-fat receptor number at the cell surface must be the result of intracellular High-fat retention of the receptor. Leptin 150 receptors are mainly localised to
the Golgi and trans-Golgi network % of control B 100 (TGN) in the cell (Fig. 2B). However,
both smaller increases in the level of SOCS3 gene expression 50 leptin induced by high-fat feeding and decreases in leptin levels during 0 fasting, resulted in an increase in Leptin Leptin receptor number on the choroid Control 1hr 1 week Ob-Rb-GFP TGN Merge plexus. High-fat feeding and fasting Low-fat Figure 2. A, changes in the level of have been shown previously to 125 [ I] leptin binding in response to high- down-regulate the transport of leptin High-fat fat diet and leptin challenge. B, the long into the brain (Kastin & Akerstrom, form of the leptin receptor coupled to Figure 3. A, the effect of high-fat diet 2000; Banks et al. 2004). One green fluorescent protein (Ob-Rb-GFP) and leptin challenge on the level of expressed in CHO cells colocalises with explanation for this counter-intuitive Ob-Rb; B, SOCS3 gene expression trans-Golgi network (TGN) specific increase in receptor number may in the arcuate nuclei (ARC) of the inmmunoreactivity. be that normal transport of leptin hypothalamus.
Physiology News | No. 78 | Spring 2010 | www.physoc.org 16 PN NEWS AND VIEWS down-regulation. The increase in Does activity in the lateral cerebellum receptor gene expression seen in the present study is prevented by the reflect predictive control of visually guided high-fat diet but is not associated with the inhibition of leptin movements? signalling via the JAK/STAT pathway How do we track a moving target accurately with our eye or as the induction of SOCS3 is not hand? In order to overcome the long neural delay in processing inhibited (Fig. 3B). This indicates that visual feedback information, it is necessary to predict the future one of the other leptin signalling position and trajectory of the target if it is to be tracked with pathways may be important in this response – but this remains to be accuracy. Predictive behaviour can be achieved through internal tested. models, and one structure that has been implicated as a key site for their operation is the cerebellum Our study points to the fact that the leptin receptor has evolved to be For activities as diverse as catching a regulated by low circulating levels ball, or reaching out to pick up a cup of leptin, whereas high circulating of coffee, the cerebellum is thought levels of leptin and a high-fat diet to play a prominent role in the may interfere with normal regulation accurate execution of visually guided of gene expression and receptor movements. But how exactly the number. cerebellum controls the interactions Nadia between our limbs and the external Cerminara Lynda M Williams1 and Ruben environment is a matter of debate. 2 Behavioural experiments have shown Nogueiras that the minimum interval needed 1Obesity and Metabolic Health for visual information to influence an feedback from the moving body part Division, Rowett Institute of ongoing movement is approximately to guide the movement. Nutrition and Health, University of 80–100 ms. This neural delay time Aberdeen, Aberdeen AB21 9SB, UK in sensory processing and motor In the context of moving our limb execution is far too long to permit towards an object, say a cup of 2Department of Physiology, effective feedback control; therefore, coffee, a forward model would School of Medicine – Instituto one must be able to predict and predict the position or velocity de Investigacion Sanitaria anticipate the position and trajectory of the limb, whereas an inverse (IDIS), University of Santiago of the target. One structure that model would transform the desired de Compostela and CIBER seems particularly critical in this trajectory of the limb into the Fisiopatología de la Obesidad y prediction process is the cerebellum. appropriate joint forces/torques. Nutrición (CIBERobn), Santiago de However, there is disagreement Compostela (A Coruña), 15782, Predictive behaviour can be achieved in the literature regarding the Spain through internal models (Miall et al. existence of inverse versus forward 1993; Wolpert et al. 1995). Broadly models in the cerebellum. On the speaking, internal models are References one hand, Purkinje cell activity in defined as neural representations regions of the cerebellum concerned Banks WA, Coon AB, Robinson SM, Moinuddin of our bodies and objects in the with eye movements have been A, Shultz JM, Nakaoke R & Morley JE (2004). external environment and can be Triglycerides induce leptin resistance at the interpreted as representing inverse blood-brain barrier. Diabetes 53, 1253–1260. of two types: forward and inverse. models (Gomi et al. 1998). On the Forward models make predictions Belouzard S, Delcroix D & Rouille Y (2004). other hand, in a recent study of Low levels of expression of leptin receptor about the behaviour of the motor non-human primates performing at the cell surface result from constitutive system and external objects a circular manual tracking task endocytosis and intracellular retention in whereas inverse models transform under various force loads, Purkinje the biosynthetic pathway. J Biol Chem 279, a desired goal into the appropriate cell activity was not altered with 28499–28508. plan of action. The cerebellum is the change in hand force and arm Kastin AJ & Akerstrom V (2000). Fasting, but thought to form internal models muscle activity that occurred as a not adrenalectomy, reduces transport of through a learning process in leptin into the brain. Peptides 21, 679–682. result of varying the loads (Pasalar et which a simulation of the desired al. 2006), leading to the conclusion Mitchell SE, Nogueriras R, Morris A, Tovar S, movement is constructed and that rather than an inverse dynamics Grant C, Cruickshank M, Rayner DV, Dieguez modified by repeated practice of the C & Williams LM (2009). Leptin receptor model of the arm, Purkinje cell gene expression and number in the brain movement. This allows us to rapidly activity represents the kinematic are regulated by leptin level and nutritional and precisely execute a desired output of arm movements. This status. J Physiol 587, 3573–3585. movement without depending kinematic representation may in http://jp.physoc.org/content/587/14/3573.full exclusively on on-line sensory fact correspond to the output of
Physiology News | No. 78 | Spring 2010 | www.physoc.org NEWS AND VIEWS PN 17
Target invisible A C (impulses/s) Discharge rate rate Discharge
-200 0 200 400 start Time (ms) Figure 1. A, representative example of a Purkinje cell that showed tonic activity during target motion. The onset of target motion occurred at time point 0. B, example of a Purkinje cell that showed significant modulation (P < 0.05, one-way ANOVA, n = 7) to a ‘preferred’ target velocity of 6.2 cm s−1. Each data point represents mean tonic discharge rate ± S.E.M. C, schematic diagram demonstrating the expected Purkinje cell activity if tonic activity that would occur when visibility of the target was occluded, if activity simply reflects actual target motion driven by the visual stimulus (blue line) or if activity is due to the construction of a forward model of its motion (red line). (Adapted from Miles et al. 2006.) A C
B D
R2 = 0.9801
Figure. 2. A and B, schematic diagram of behavioural task. Cats were trained to perform a visually guided reaching task in the dark in which a tube, dimly lit by a ring of LEDs and containing a food reward, was initially stationary 7 cm to the left of centre. B, in a ‘go’ trial, the tube started to move horizontally in the rightwards direction at a constant velocity of 6.2 cm s-1. After an interval of approximately 600 ms after the commencement of target motion, the LEDs brightened to cue the animal to make a reach with its left forelimb, ipsilateral to the cerebellar recording, to retrieve a food reward from the tube. C, peri-event time histogram (PETH) showing an example Purkinje cell which displayed a tonic increase in simple spike activity in relation to target motion. In one half of the trials, the moving target disappeared for 300 ms during target motion. Target denial occurred 200 ms after the onset of target motion. Dotted vertical line at 0.6 s represents ‘go’ signal. D, comparison of responses during target denial with no denial control. No significant change (paired t test, P > 0.05, n = 10). Line represents unity. (Adapted from Cerminara et al. 2009.)
Physiology News | No. 78 | Spring 2010 | www.physoc.org 18 PN NEWS AND VIEWS a forward model that predicts the the operation of a forward model? model of target movement has been consequences of limb movements. Alternatively, was the neuronal constructed which predicts the Therefore, in relation to control activity simply coding the on-line target’s velocity and position and of parts of the body, such as the motion of the target driven by the thereby maintains neural activity in eyes or limbs, the debate between visual stimulus? the absence of sensory information. forward and inverse models remains Such a mechanism is likely to be unresolved. In order to distinguish between important for movement planning these two possibilities, temporary and control for the interception of One way to inform the debate is to visual denial of the target can be a moving object – just the sort of seek evidence for the existence of used. Whilst invisible, the tonic skilled movement that is severely internal models in the cerebellum increase in discharge rate usually affected when the cerebellum is of the movement of objects in the seen whilst the visible target is damaged. Further experiments are external world. The situation here moving would be expected to required to address the learning is simpler; if an internal model of disappear if the cells were being process involved in acquiring such an external moving object exists, passively driven by the sensory models. it can only be of the forward type, stimulus whereas such activity would making predictions about the be expected to survive if a forward Nadia L Cerminara object’s future position and velocity. model of target motion had been Department of Physiology and When pursuing a moving target, it formed (Fig. 1C). Pharmacology, School of Medical is necessary to overcome the delays Sciences, University of Bristol, Again we used single unit recordings in visual feedback by predicting the Bristol, UK future location of the target based in cats trained to perform a on its motion. It has been suggested predictable visually guided reaching References that on-line visual information is task. Cats were trained to reach Barborica A & Ferrera VP (2003). Estimating combined with a representation (after receipt of a ‘go’ signal) into invisible target speed from neuronal activity of target kinematics to make an a moving visual target travelling in monkey frontal eye field. Nat Neurosci 6, 66–74. internal model and hence predict horizontally at a constant velocity. future target location (Barborica & The target for reach consisted of Cerminara NL, Apps R & Marple-Horvat DE a hollow Perspex tube dimly lit (2009). An internal model of a moving visual Ferrera, 2003). Indirect evidence for target in the lateral cerebellum. J Physiol 587, the operation of internal models in by a ring of LEDs. The tube was 429–442. the lateral cerebellum of objects and initially stationary 7 cm to the left http://jp.physoc.org/content/587/2/429.long tools in the external world has been of centre (as viewed by the cat) at Gomi H, Shidara M, Takemura A, Inoue Y, obtained in human imaging studies a comfortable height for reaching Kawano K & Kawato M (1998). Temporal firing (Fig. 2A). The tube then moved patterns of Purkinje cells in the cerebellar (Imamizu et al. 2000). However, to ventral paraflocculus during ocular following obtain direct evidence recordings at a constant velocity rightwards responses in monkeys I. Simple spikes. J from individual cerebellar neurones across the cat’s visual field (Fig. 2B). Neurophysiol 80, 818–831. are required. Experiments were conducted Imamizu H, Miyauchi S, Tamada T, Sasaki without ambient illumination Y, Takino R, Putz B, Yoshioka T & Kawato M Previous work from our laboratory in a light-proof room. Thus, the (2000). Human cerebellar activity reflecting (Miles et al. 2006) in cats trained to only source of visual information an acquired internal model of a new tool. Nature 403, 192–195. perform a visually guided reach– available to the cat was from the retrieval task has shown that Purkinje Miall RC, Weir DJ, Wolpert DM & Stein JF target LEDs. At various stages of the (1993). Is the cerebellum a Smith predictor? J cells in the lateral cerebellum, a target’s motion, illumination of the Mot Behav 25, 203–216. region known to be involved in the ring of LEDs around the tube was Miles OB, Cerminara NL & Marple-Horvat DE visual guidance of movement (Stein temporarily extinguished during (2006). Purkinje cells in the lateral cerebellum & Glickstein, 1992), were responsive which time the animal was in total of the cat encode visual events and target to the on-going motion of the visual darkness. motion during visually guided reaching. J target, displaying tonically altered Physiol 571, 619–637. rates of simple spike discharge for For target-related Purkinje cells that Pasalar S, Roitman AV, Durfee WK & Ebner as long as the target was moving displayed tonically altered simple TJ (2006). Force field effects on cerebellar Purkinje cell discharge with implications for (Fig. 1A). The altered tonic discharge spike activity during on-going internal models. Nat Neurosci 9, 1404–1411. movement of the visual target, rate was found to encode the speed Stein JF & Glickstein M (1992). Role of the of the target, as individual Purkinje there was a similar pattern of tonic cerebellum in visual guidance of movement. cells displayed a ‘preferred’ target activity when the cat’s view of the Physiol Rev 72, 967–1017. velocity when tested against a range target was occluded (Fig. 2C and Wolpert DM, Ghahramani Z & Jordan MI of speeds (Fig. 1B). Since the cats D). This result therefore shows that (1995). An internal model for sensorimotor were familiar with the motion of visual feedback is not necessary to integration. Science 269, 1880–1882. the external target which moved maintain the pattern of discharge. Acknowledgements in a predictable fashion, could this Instead, the finding is consistent The research was supported by the BBSRC and pattern of neural activity reflect with the hypothesis that a forward The Wellcome Trust.
Physiology News | No. 78 | Spring 2010 | www.physoc.org NEWS AND VIEWS PN 19
Prometheus’ giblets Chalones were at one time hypothetical factors that once secreted, controlled tissue regeneration and defined its ultimate size. Myostatin is just such a factor and although its ability to attenuate the growth of skeletal muscle is well known, recent studies suggest that it not only regulates cardiac muscle growth, but function as well
Chained to a rock and forced to null hearts to date the gestalt endure the eternal agony of having of which clearly indicates that his liver ripped from his abdomen myostatin is a negative regulator of and devoured by a winged leviathan, physiological cardiac hypertrophy Prometheus may have regretted and, for the first time, excitation– mankind’s gift of fire against Zeus’ contraction coupling (Rodgers wishes. Being immortal, he endured et al. 2009). Myostatin inhibited this torture daily, for, as we all basal and insulin-like growth factor know, the liver regenerates. Ancient Buel D (IGF)-stimulated cardiomyoblast Rodgers Greeks, by contrast, may not have proliferation in a dose-dependent known of chalones (pronounced other aspects of myostatin biology manner. It also attenuated retinoic ‘kay lones’, Greek for ‘to slacken’), that until recently were overlooked. acid-stimulated differentiation while secreted factors that inhibit tissue our cell culture system was found growth and control the regenerative Several lines of evidence suggest to express a full complement of that myostatin may also regulate process, in this case the liver’s, but myostatin receptors and binding cardiac muscle (Rodgers & Garikipati, they clearly understood that even proteins that matched mature 2008). Its expression was identified titans have bad days. in hearts of different mammalian, cardiac muscle. Myostatin null hearts, normalized to tail length, The chalone–Prometheus association avian and fish species and it increases progressively as chick were heavier than wild-type hearts at is discussed almost as often as the all ages and in both sexes (Fig. 2A). term chalone itself as both are hearts develop. It also increases in some models of pathological cardiac These results were confirmed by commonly used to introduce the hypertrophy. Myostatin inhibits echocardiography, which also topic of liver regeneration. This proliferation and protein synthesis indicated that the larger heart process, however, isn’t limited to in a variety of cardiomyoblast cell mass was due to eccentric rather the liver per se as other tissues, culture models and reduces cardiac than concentric hypertrophy as the skeletal muscle for example, also muscle mass when overexpressed internal diameters and volumes secrete factors that ultimately limit in hearts of transgenic mice (Reisz- were larger in myostatin null hearts their growth. Indeed, myostatin Porszasz et al. 2003). However, despite similar wall thickness is an extremely potent negative preliminary studies reported measurements (Fig. 2B). This is regulator of different growth conflicting results on differences in an important distinction as the processes that contribute to the size heart size between wild-type and compensatory response to large and functionality of skeletal muscle myostatin null mice (Rodgers & increases in skeletal muscle mass, Garikipati, 2008), suggesting that (Rodgers & Garikipati, 2008). The which occurs in myostatin null null hearts could be larger or smaller, hypermuscularity of the myostatin mice, normally produces concentric null phenotype (Fig. 1) has been depending on sex or age, than wild-type hearts. A more thorough hypertrophy. All of these results described in a variety of mammals, assessment of myostatin’s ability to together indicate that myostatin including humans, and is responsible regulate cardiac muscle growth and directly and negatively regulates for the ‘double muscling’ that occurs function was therefore needed. cardiac muscle growth. They also in some domestic breeds. The confirm previous studies with similar extreme nature of this phenotype, We recently reported the most conclusions (Rodgers & Garikipati, however, may have overshadowed comprehensive analysis of myostatin 2008).
Figure 1. ‘Double muscled’ phenotype of myostatin null animals. Forelimb musculature of 5-month-old myostatin null (A) and wild- type (B) mice. Inset are jaw masseter muscles. C, Piedmontese bull, the first breed to include a null-genotype (full or partial for mstn) as a ‘mandatory registry requirement’. Picture reproduced with permission from the North American Piedmontese Cattle Association (NAPA, www.piedmontese.org).
Physiology News | No. 78 | Spring 2010 | www.physoc.org 20 PN NEWS AND VIEWS
Figure 2. Physiological cardiac hypertrophy and enhanced excitation–contraction coupling in myostatin null hearts (Rodgers et al. 2009). A, heart weight/tail length (HW/TL) ratios in wild-type (WT) and myostatin null (mstn–/–) mice of different ages. Female mice are shown, although mstn–/– hearts were also larger in male mice. Echocardiography was used to assess cardiac performance and mass in anaesthetized mice before (B) and after (C) administering 10 mg kg-1 isoproterenol (ISO). Data in C are represented as % change from before ISO treatment and asterisks denote significant differences inB and C (P ≤ 0.05). LVIDd/s, left ventricle internal diameters at diastole and systole; IVSd, intraventricular septum; LVWd, LV wall dimension; Diast and Syst vol, LV end diastolic or systolic volume; FS, fractional shortening; EF, ejection fraction, St. vol, stroke volume; HR, heart 2+ –/– rate). D, confocal line scan images of evoked [Ca ]i transients (1 Hz) in WT and mstn ventricular myocytes 2+ before and after (–/+) 100 nM ISO. E, time course of [Ca ]i (top) and cell shortening (CS) in representative WT and mstn–/– ventricular myocytes before and after ISO. Transients were evoked with field stimulation (1 Hz).
Most notably, we also discovered occurs when hearts hypertrophy not alone as most organs possess at that myostatin null cardiac muscle from pathological conditions, as with least a limited capacity to regenerate was functionally superior to chronic hypertension or following some or all of their tissues. This that of wild-type mice during an myocardial infarction. Cardiac includes another giblet, the heart, isoproterenol (ISO) stress test. In hypertrophy itself is not inherently whose growth is regulated by fact, changes in ISO-stimulated bad as it is also an adaptive response the chalone myostatin. One has cardiac output, as indicated by to exercise. Myostatin null mice, to imagine, therefore, whether several parameters (Fig. 2C), were therefore, possess physiological, not Prometheus would have suffered less significantly greater in myostatin pathological, cardiac hypertrophy. had he lacked myostatin. He would null mice. This included heart rate have at least been in better shape to and suggested that excitation– Myostatin-blocking technologies fight off that wretched bird. contraction coupling may also (e.g. immunoneutralization, soluble receptors, etc.) are currently be enhanced. We confirmed this Buel D Rodgers hypothesis in vitro using several being developed in both academic biophysical assays and ultimately and industrial labs and all have Department of Animal Sciences and 2+ School of Molecular Biosciences, determined that [Ca ]i transients produced very promising results (movements between intracellular (Rodgers & Garikipati, 2008). None, Washington State University, stores) and total cellular loads however, has thoroughly explored Pullman, WA 99164, USA were greater in primary ventricular their potential in treating cardiac myocytes from myostatin null pathologies, and have focused References hearts. Furthermore, these primarily on muscular dystrophies Guo T, Jou W, Chanturiya T, Portas J, Gavrilova differences were associated with and sarcopenia. Recent studies also O & McPherron AC (2009). Myostatin inhibition in muscle, but not adipose tissue, enhanced contractility in isolated suggest that attenuating myostatin decreases fat mass and improves insulin cells (Fig. 2D and E). The superior action could potentially improve sensitivity. PLoS One 4, e4937. β-adrenergic responsiveness and insulin sensitivity and reduce fat Reisz-Porszasz S, Bhasin S, Artaza JN, Shen R, cardiac output in myostatin null mass in obese subjects, most Sinha-Hikim I, Hogue A, Fielder TJ & Gonzalez- hearts was therefore due in part probably by increasing muscle Cadavid NF (2003). Lower skeletal muscle to differences in Ca2+ handling and mass and as a consequence, the mass in male transgenic mice with muscle- specific overexpression of myostatin. Am J excitation–contraction coupling. resting energy expenditure (Guo Physiol Endocrinol Metab 285, E876–E888. et al. 2009). It is not unreasonable, Normalized tension, ATPase activity Rodgers BD & Garikipati DK (2008). Clinical, therefore, to presume that such agricultural, and evolutionary biology of and the tension–cost relationship myostatin-blocking technologies myostatin: a comparative review. Endocr Rev of skinned fibres from wild-type may also help treat a variety of 29, 513–534. and null hearts were identical and cardiac pathologies as well as two Rodgers BD, Interlichia JP, Garikipati DK, previous studies determined that exacerbating conditions – obesity Mamidi R, Chandra M, Nelson OL, Murry CE & Santana LF (2009). Myostatin represses the latter were histologically normal. and type 2 diabetes. We additionally determined that physiological hypertrophy of the heart and excitation–contraction coupling. J Physiol 587, myostatin null hearts do not possess The liver may be the most fabled 4873–4886. the fetal gene expression profile that regenerative organ. However, it is http://jp.physoc.org/content/587/20/4873.long
Physiology News | No. 78 | Spring 2010 | www.physoc.org NEWS AND VIEWS PN 21
Bloodless revolution Subtle paracrine interactions between minor depots and contiguous tissues are restoring the reputation of adipose tissue, best known for its bulk and disease-causing properties. Micromanagement of fatty acids supports fast, efficient immune responses that avoid competition with other lipid-utilizing tissues. Such roles explain aspects of the gross anatomy of mammalian adipose tissue, long thought to be inexplicable
Aversion to adipose anatomy surrounding adipocytes. The Adipose tissue’s ‘image’ has had omentum, a uniquely mammalian a more thorough ‘makeover’ structure, is a patchwork of during the past 15 years than that adipose and immune cells. Under of any other organ or tissue. For the insidious influence of adipose- physiologists, proteomics and the aversed anatomists (Fig. 1), most enthusiasm of the pharmaceutical textbooks of immunology described industry have made secreted Caroline Pond these facts very briefly, if at all peptides, leptin, visfatin, resistin, (Harvey, 2008). adiponectin and many more, the obvious deviants like metabolically In the early 1990s, the study of best-known aspect of this revolution. inert, structural depots, all adipose neurohumoral activity of perivascular But at last, anatomists are trying tissue was presumed to respond adipose tissue around rat aorta was to explain the tissue’s organisation similarly to blood-borne and neural prompted by the observation that and anatomical relations, topics that signals. ‘virtually every blood vessel in the concern surgeons, beauticians and body is surrounded to some degree ordinary people dissatisfied with Lymphoid structures of all by adipose tissue’ (Soltis & Cassis, their figures but not with their body endothermic vertebrates are closely 1991). At about the same time, we mass. associated with adipose tissue (Pond, began to investigate experimentally 2003). In mammals, the lymph ducts One of the major triumphs of why epicardial and pericardial run through the adipose tissue and biology between the late eighteenth adipocytes (Marchington et al. 1989; divide into numerous fine branches century and mid-twentieth century Marchington & Pond, 1990) develop near the nodes, thereby coming was showing that the arrangement early in life and are not depleted in into contact with many of the of major organs in each group of naturally lean wild animals. We were animals follows a consistent body stumped by the most basic problem: plan. In cases such as snakes and laboratory rodents have variable, whales, where one or both pairs often negligible, quantities of cardiac of limbs are absent, remnants are adipose tissue. Advances in MRI and detectable during development other scanning systems at the new and sometimes throughout life millennium enabled the site-specific as vestigial structures. Many of properties of these minor adipose the hox genes controlling these depots to take centre stage in clinical major anatomical changes have and basic cardiovascular physiology been identified. But many adipose (Iacobellis et al. 2008). Although depots seem to appear and long regarded as pathological, the disappear without such formalities, cardiac depots are at last achieving capricious variation that demoralised respectability as integral, natural comparative anatomists: the topic is components of the heart (Fox et not addressed in Edwin Goodrich’s al. 2009); perinodal adipose tissue 1930 treatise, Studies on the Structure deserves similar status. and Development of Vertebrates. This omission led to the notion Figure 1. The source of the problem. Minor depots, major players: lipids that its distribution and anatomical 19th century prosection made for The for lymph nodes relations are without functional or Royal College of Surgeons’ Hunterian Many, possibly most, of the fatty phylogenetic significance. Goodrich’s Museum of the popliteal ‘space’ in the acids incorporated into lipids in distaste for anatomically unruly right hind leg of a dog, showing the lymph node lymphoid cells that tissues, plus the widening gap ‘important’ components of the lymph are newly formed in response to and blood systems. Blood vessels and between comparative and functional immune stimulation are derived lymph nodes shorn of their adipose anatomy and rising concern about tissue still feature in modern textbooks, from triacylglycerols in perinodal obesity, focussed attention on just perpetuating the misleading notion that adipocytes (Pond, 2007, 2009). one or two large, readily accessible perivascular and perinodal adipose tissue Site-specific properties of perinodal adipose depots. Except for a few are irrelevant or abnormal. adipocytes equip them to supply
Physiology News | No. 78 | Spring 2010 | www.physoc.org 22 PN NEWS AND VIEWS Figure 2(b)
A B
Part of popliteal lymph node
Figure 2. Perinodal adipose tissue functions as part of the lymph node. Thick section of part of a rat popliteal lymph node and its perinodal adipose tissue 1 h after subcutaneous injection of 2 mg lipopolysaccharide and staining with immunofluorescent antibody to type 1 receptors to tumour necrosis factor-α seen under (A) bright field (B) UV light. Perinodal adipocytes are indistinguishable from others until cytokine receptors appear on the surface, some within minutes of activation of the enclosed lymph node (MacQueen & Pond, 1998). lymphoid cells. Spontaneous interactions between adipocytes and experiment to explore recovery lipolysis in adipocytes within 2 mm the lymphoid cells that they supply. from simulated low-level chronic of lymph node(s) draining the site inflammation, the numbers of of the immune stimulus increases Lymph node-derived dendritic dendritic cells recovered from the within an hour of an experimentally cells suppress lipolysis in perinodal locally stimulating lymph node and elicited immune response, reaches a adipocytes but those that permeate its perinodal adipose tissue rose at maximum after about 6 h and then the adipose tissue stimulate lipolysis, least tenfold within 4 weeks and wanes, disappearing totally after especially after minor, local immune remained higher long after this about 24 h. But the effect can be stimulation enabling lymph node regime was applied (Fig. 3). Perhaps prolonged, possibly indefinitely, and lymphocytes and tissue dendritic surprisingly, perinodal adipose elicited in adipocytes situated further cells to acquire fatty acids from tissue around remote lymph nodes, from the lymph node, by repeated the contiguous adipocytes. Their especially those in the abdomen, immune stimulation. The appearance triacylglycerols contain more responded similarly (Fig. 4). of more receptors for tumour long-chain polyunsaturated fatty acids, precursors for eicosanoids and necrosis factor-α on perinodal Prolonged, low-level immune docosanoids. Chronic inflammation adipocytes follows a similar time stimulation induces the local alters their composition, and hence course (Fig. 2). Perinodal adipocytes formation of more adipocytes, that of the lymphoid cells they respond much more strongly than especially adjacent to the inflamed supply, counteracting adverse effects those not anatomically contiguous lymph node. This mechanism may of dietary lipids. to lymphoid structures to tumour contribute to hypertrophy of the mesentery and omentum in chronic necrosis factor-α, interleukin-4 and The involvement of perinodal inflammatory diseases such as interleukin-6 and probably other adipocytes in immune responses HIV infection, and in smokers. The cytokines. These signal molecules not only begins within minutes may mediate the paracrine but can persist for months. In a rat site-specific differences in fatty acid composition of lipids in the mesenteric adipose tissue expected Thousands from animal studies are absent from of DCs 2 Crohn’s disease patients, though collected they were found in similar samples over 4 h from the controls (Westcott et al. per 50 mg 1 adipose 2005). The composition of lymphoid tissue cells in mesenteric lymph nodes resembles that of the adjacent Control 4 weeks No rest +4 weeks +8 weeks +12 weeks perinodal adipose tissue in the 20 μg LPS rest rest rest controls, but not in the diseased 20 μg LPS 3 times a week for 8 weeks patients, which suggests that their Figure 3. Perinodal adipose tissue stays alert. Mild chronic immune stimulation (local adipocytes are not supplying fatty subcutaneous injection of 20 mg lipopolysaccharide (LPS) 3 times a week) increases acids to cells in the adjacent lymph interchelated dendritic cells (DCs) throughout the popliteal adipose depot, most in nodes. Lipids from the lymph node the perinodal, within 2 mm of the large popliteal lymph node, but significant in the lymphoid cells from Crohn’s disease ‘middle’ sample, about 5 mm from the node, and the ‘remote’ sample more than patients contain much less of the 10 mm away. Recovery is surprisingly slow: numbers of CCL21 (C6kine)-activated eicosanoid precursor arachidonic acid dendritic cells migrating from tissue samples are still higher more than 8 weeks after experimental inflammation ended. (Data from Sadler et al. 2005.) (C20:4n-6) than the controls.
Physiology News | No. 78 | Spring 2010 | www.physoc.org NEWS AND VIEWS PN 23
Fox CS, Gona P, Hoffmann U, Porter SA, Salton 10 CJ, Massaro JM, Levy D, Larson MG, D’Agostino RB, O’Donnell CJ & Manning WJ (2009). Pericardial fat, intrathoracic fat, and measures 8 of left ventricular structure and function: the Hundreds Framingham Heart Study. Circulation 119, of DCs 1586–1591. collected 6 over 4 h Gehring S, Gregory SH, Wintermeyer P, Martin per 50 mg MS, Aloman C & Wands JR (2008). Generation and characterization of an immunogenic adipose 4 tissue dendritic cell population. J Immunol Methods 332, 18–30. 2 Harvey NL (2008). The link between lymphatic function and adipose biology. Ann N Y Acad Sci 1131, 82–88.
Control 4 weeks No rest +4 weeks +8 weeks +12 weeks Iacobellis G, Gao YJ & Sharma AM (2008). Do 20 μg LPS rest rest rest cardiac and perivascular adipose tissue play a 20 μg LPS 3 times a week for 8 weeks role in atherosclerosis? Curr Diab Rep 8, 20–24. Figure 4. Even remote, mild inflammation gradually gets to the guts. Mild chronic MacQueen HA & Pond CM (1998). immune stimulation of the skin over the hind leg increases interchelated dendritic Immunofluorescent localisation of tumour cells in the adipose tissue around remote as well as local lymph nodes. This effect necrosis factor-α receptors on the popliteal lymph node and the surrounding adipose is substantial in the mesentery and milky spot-rich areas of the omentum, where it tissue following a simulated immune persists for at least 3 months after experimental inflammation ends, but is almost challenge. J Anat 192, 223–231. undetectable in the more frequently sampled mesenteric adipose tissue located Marchington JM, Mattacks CA & Pond CM more than 10 mm from a lymph node. It may be among the ways that chronic or (1989). Adipose tissue in the mammalian repeated inflammation slowly induces hypertrophy of intra-abdominal adipose tissue. heart and pericardium: structure, foetal (Data from Sadler et al. 2005.) development and biochemical properties. Comp Biochem Physiol B 94, 225–232. The discrepancy between the emancipates immune function from composition of perinodal adipocytes fluctuations in food quantity and Marchington JM & Pond CM (1990). Site- specific properties of pericardial and and that of adjacent lymphoid composition. Energy-consuming epicardial adipose tissue: the effects of insulin cells contrasts with the concept of systemic responses to immune and high-fat feeding on lipogenesis and the paracrine nutrition of lymphoid cells, challenges, such as fever, avoid incorporation of fatty acids in vitro. Int J Obes but is consistent with reports that competition for essential lipids with 14, 1013–1022. blood-borne mononuclear cells from proliferating lymphoid cells; anorexia Pond CM (2003). Paracrine interactions of Crohn’s disease patients contain may help to ‘put adipose tissue in mammalian adipose tissue. J Exp Zool A Comp Exp Biol 295, 99–110. more, not less, n-3 polyunsaturated charge’ of lipid management during fatty acids. General defects in the crisis. Supplying fatty acids of Pond CM (2007). Interactions of adipose and lymphoid tissues. In Nutrition and Health: perinodal adipose tissue leading to slightly different composition also Adipose tissue and Adipokines in Health and impaired immune function could provides local sources of structural, Disease, pp. 133–150, eds Fantuzzi, Giamila, explain the association between the and perhaps also functional, diversity Mazzone & Theodore. Humana Press Inc. bowel disorders and other chronic of lymphoid cells that hitherto Pond CM (2009). Paracrine provision of lipids diseases such as arthritis, eczema have been classified by genes and in the immune system. Curr Immunol Rev 5, and rhinitis (Book et al. 2003). proteins (Gehring et al. 2008). 150–160. Could ‘fat wrapping’, the distinctive Paracrine interactions, especially Sadler D, Mattacks CA & Pond CM (2005). but as yet unexplained feature of those involving only a small fraction Changes in adipocytes and dendritic cells in of the total adipose tissue, cannot lymph node containing adipose depots during Crohn’s disease, be adipose tissue’s and after many weeks of mild inflammation. J long-term response to persistent easily be detected as changes in Anat 207, 761–781 blood composition. But blood supply signals from its client immune cells Soltis EE & Cassis LA (1991). Influence of for important fatty acids that it is to perinodal adipose tissue increases perivascular adipose tissue on rat aortic unable to supply? during inflammation so they could smooth muscle responsiveness. Clin Exp probably be manipulated by blood- Hypertens A 13, 277–296. Paracrine provision: private, borne drugs. Westcott EDA, Windsor ACJ, Mattacks CA, personalised, potent Pond CM & Knight SC (2005). Fatty acid Caroline M Pond compositions of lipids in mesenteric adipose By ensuring that specific, possibly tissue and lymphoid cells in patients with and scarce, fatty acids reach the cells Department of Life Sciences, The without Crohn’s disease and their therapeutic that really need them when and Open University, Milton Keynes, implications. Inflamm Bowel Dis 11, 820–827. where required, perinodal adipocytes MK7 6AA, UK may be compared to tRNA that References Acknowledgements marshals amino acids into position Book DT, Smith TL, McNamar JP, Saeian The Leverhulme Trust, Bristol-Myers Squibb or chaperonins that help proteins K, Binion DG & Toohill RJ (2003). Chronic (USA), The Open University Trustees’ fund sinonasal disease in patients with and The North West London Hospital fold correctly. Local provisioning inflammatory bowel disease. Am J Rhinol 17, Trust supported many of the experiments of lymphoid tissues partially 87–90. mentioned in this article.
Physiology News | No. 78 | Spring 2010 | www.physoc.org 24 PN NEWS AND VIEWS
Exercise-induced lipid mobilization in humans: the role of catecholamines revisited Bidirectional communication exists between the central nervous system and white adipose tissue. Here we discuss the relative contribution of the various factors involved in exercise- induced lipid mobilization in humans, reassessing the role of catecholamines A number of questions but at very low levels of innervation concerning the regulation of of adipocytes. Moreover, the lipid mobilization (i.e. hydrolysis/ sympathetic nervous system drive lipolysis of triglycerides stored in to the various body fat deposits is the adipocytes) have been mostly not homogenous. In humans, up investigated in rodents, the adipose until recently, the major regulators tissue of which clearly differs from of lipid mobilization (i.e. hydrolysis that of humans. Lipolysis is such of triglycerides stored in the Vladimir Stich (left) and Max Lafontan an important metabolic event that adipocytes) were considered to be control of lipid mobilization during a number of redundant factors the catecholamines (adrenaline physical exercise has been less and pathways contribute to its (ephinephrine) and noradrenaline (norepinephrine)) as the stimulators convincingly established. Exercise physiological regulation (Lafontan & of lipolysis and insulin for its is an excellent physiological Langin, 2009) (Fig. 1). The debated inhibition. challenge to promote sympathetic questions concerning the role of nervous system activation; there the sympathetic nervous system In humans, the unquestionable is no doubt that it contributes to in the control of white adipose impact of both catecholamines on the control of lipid mobilization, tissue lipolysis have recently been lipid mobilization is observed when since plasma levels of adrenaline reviewed by Bartness et al. (2009). they are infused intravenously. and noradrenaline are increased White adipose tissue is innervated However, the relative contribution during exercise. They stimulate by the sympathetic nervous system of both amines in the physiological both fat cell β1-2- and α2A-adrenergic receptors, which enhance and inhibit lipolysis, respectively. In fact, the simultaneous activation of both receptors modulates the intracellular cAMP concentration, which activates cAMP-dependent protein kinase, leading to the phosphorylation and activation of the hormone-sensitive lipase (Lafontan & Langin, 2009). Growth hormone (GH) and other putative lipolytic candidates (i.e. natriuretic peptides or IL-6) have also been suspected to contribute (Fig. 1). In addition, exercise is also well known to promote inhibition of insulin release that is related to sympathetic nervous system-mediated inhibition of insulin release at the level of the pancreatic β-cells. Suppression of Figure 1. Hormonal factors involved in the control of exercise-induced lipid the anti-lipolytic effect of insulin is mobilization in humans. Catecholamines (adrenaline and noradrenaline) can act on important to enhance the lipolytic
fat cell β1,2- and α2A-adrenergic receptors according to a complex interplay (see Fig. 2) activity of the fat cells. Nevertheless, and promote acute stimulation of lipolysis (see discussion). Natriuretic peptides (ANP contrary to former beliefs, studies and BNP) are released by the heart cardiomyocytes during exercise. Their release have questioned the importance of is increased after the oral administration of a β-adrenergic receptor antagonist the contribution of catecholamines. given before exercise. The secretion of insulin, the potent anti-lipolytic hormone, It has been shown, at low and is suppressed by noradrenaline released during physical exercise. Growth hormone moderate intensities of exercise, (GH) is also released by exercise but its effect on lipid mobilization is not acute. that under an oral -adrenergic Increased circulating interleukin-6 (IL-6) levels observed during exercise originate β from skeletal muscle; the lipolytic effect of IL-6 is weak and not acute. Neither agent receptor blockade associated with (GH and IL-6) can be considered to contribute to the regulation of lipid mobilization a local perfusion of propranolol, under the experimental conditions used by de Glisezinski et al. (2009). the exercise-induced increase of
Physiology News | No. 78 | Spring 2010 | www.physoc.org NEWS AND VIEWS PN 25 lipolysis was diminished but not The relative contribution of the were suppressed. An intravenous completely inhibited (Moro et al. various factors involved in the infusion of the somatostatin 2004). Based on previous studies control of exercise-induced lipid analogue, octreotide, was given demonstrating the lipolytic role of mobilization still remains an open before, during and after exercise; natriuretic peptides (Sengenes et al. and intricate challenge. A recent it potently inhibited insulin and 2000) (Fig. 2), the residual lipolysis study investigating this complex GH secretion during exercise. In remaining under full β-adrenergic question has allowed the delineation addition, the noticeable point was receptor blockade was attributed of the relative contribution of that adrenaline secretion was also to these peptides. In fact, plasma adrenaline and noradrenaline in the blocked by octreotide treatment levels of natriuretic peptides increase control of exercise-induced lipid while the exercise-induced increase during an acute bout of physical mobilization in man to be elucidated in noradrenaline release was not exercise, and an enhanced release of (de Glisezinski et al. 2009), and modified (Fig. 3c). Thus, octreotide these peptides occurs when exercise revealed the importance of administration provides a unique is performed under oral β-adrenergic adrenaline instead of noradrenaline. condition whereby the impact receptor blockade (Moro et al. 2004). of adrenaline and noradrenaline Further studies have shown that A pharmacological strategy was on lipolysis could be dissociated. natriuretic peptides are physiological used to support this physiological Experiments were performed on contributors of exercise-induced lipid approach and eliminate the healthy lean young men, fasted mobilization in various situations intervention of some factors. overnight and performing exercise in humans, though this system is Firstly, the catecholaminergic bouts over 60 min at 50% of their not operative in rodents and dogs responsiveness was studied peak oxygen uptake during placebo (Lafontan et al. 2008). when insulin and GH secretions or octreotide administration.
Figure 2. Major pathways involved in the stimulation of human fat cell lipolysis. Signal transduction
pathways for catecholamines via β1-2- and α2A-adrenergic receptors, autacoids- and metabolite-driven inhibitory receptors and atrial natriuretic peptides (ANP and BNP) via type A receptor (NPR-A). Protein kinases (PKA and PKG (cGK-I)) are involved in target proteins phosphorylation (perilipin and HSL). ATGL possesses an exclusive triglyceride lipase activity; it is activated by ABHD5. Perilipin phosphorylation induces an important physical alteration of the lipid droplet surface that facilitates the action of ATGL and HSL on triglycerides and the initiation of lipolysis. Perilipin phosphorylation also releases ABHD5, the activator of ATGL. HSL phosphorylation promotes its translocation from the cytosol to the surface of the lipid droplet. MGL hydrolyses monoacylglycerols. Docking of adipocyte lipid binding protein (FABP4) to HSL favours the outflow from the cell of NEFAs released by the hydrolysis of triglycerides. Glycerol outflow is facilitated by aquaporin-7 present in the adipocyte. Insulin, via stimulation of fat cell insulin receptors and phosphodiesterase-3B (PDE-3B) activation, promotes cAMP degradation and anti-lipolytic effects. It is not active on cGMP-dependent pathways (not shown in the diagram). ABHD5, ab-hydrolase domain-containing protein; ANP, atrial natriuretic peptide; ATGL, adipose triglyceride lipase; BNP, B type natriuretic peptide; FABP4, adipocyte fatty acid binding protein 4; GC, guanylyl cyclase; Gi, inhibitory GTP-binding protein; Gs, stimulatory GTP-binding protein; HSL, hormone-sensitive lipase; MGL, monoacylglycerol lipase; NEFA, non-esterified fatty acid; NPR-A, type A natriuretic peptide receptor; NPR-C, type C natriuretic peptide receptor.
Physiology News | No. 78 | Spring 2010 | www.physoc.org 26 PN NEWS AND VIEWS
Microdialysis was used to monitor blunting effect of α2A-adrenergic while noradrenaline increment local lipid mobilization (i.e. glycerol receptor stimulation. The blockade persists (Fig. 3c). release) in subcutaneous adipose of α2A-adrenergic receptors removes tissue during the exercise. It is the lipolysis-inhibiting part of the Based on these results and on a well-recognized method for catecholamine action during exercise some previous studies (Stallknecht mechanistic explorations of adipose (Stich et al. 2000). If, in addition to et al. 2001), it is suggested that it tissue responsiveness in vivo. that, when the local β-adrenergic is plasma adrenaline rather than receptor blockade was performed, noradrenaline which is the main Local blockade of fat cell β- and the exercise-induced lipolysis was adrenergic factor involved in α2A-adrenergic receptors was carried reduced in control (Fig. 3a) but not exercise-induced lipolysis, at least out in situ by direct perfusion of in the octreotide condition (Fig. 3c). in human subcutaneous adipose the β- (i.e. propranolol) and α2A- This suggests that the β-adrenergic tissue. It must be remembered (i.e. phentolamine) antagonists stimulation of lipolysis during that adrenaline is known to through the microdialysis probes exercise is mediated by adrenaline possess the highest affinity, when to investigate the part played by but not noradrenaline. In fact, compared with noradrenaline, for catecholamines during exercise. both plasma levels of adrenaline β2- and α2A-adrenergic receptors, The physiological stimulation of and noradrenaline ‘normally’ the major adrenergic receptors of adipocyte α2-adrenergic receptors increase when physical exercise is the human adipocytes (Lafontan during exercise-induced sympathetic performed in control conditions. & Berlan, 1982). In addition, the nervous system activation Under octreotide infusion the persistence of lipid mobilization contributes to the blunted lipolysis. exercise-induced increase of plasma after the full blockade of fat cell Phentolamine suppresses the adrenaline is completely blocked adrenergic receptors suggests
Figure 3. Impact of physical exercise (60 min at 50% of peak oxygen uptake) on lipid mobilization in placebo or octreotide-treated lean human subjects. Dialysate glycerol concentration from subcutaneous adipose tissue measured at rest, during exercise and the recovery period under intravenous infusion of placebo (a) or octreotide administration (30 ng–1 min–1 kg–1) (b) in lean subjects. One probe was perfused with Ringer solution plus phentolamine (100 µmol l–1) and the second one with Ringer solution plus phentolamine (100 µmol l–1) plus propranolol (100 µmol l–1). Data are expressed as mean ± S.E.M. *P < 0.05, significant when compared to values obtained in the probe with phentolamine plus propranolol and the probe with phentolamine alone. c, plasma noradrenaline and adrenaline (norepinephrine and epinephrine) concentrations at rest, during exercise and the recovery period under intravenous infusion of placebo or octreotide (30 ng min– 1 kg–1) in lean subjects. Data are expressed as mean ± S.E.M. *P < 0.05, significant when compared to values obtained with octreotide infusion. Octreotide treatment suppresses exercise-induced adrenaline release while having no impact on noradrenaline release (c). When adrenaline is not released, the β-adrenergic component of the lipid mobilizing response disappears completely although plasma noradrenaline levels are elevated.
Physiology News | No. 78 | Spring 2010 | www.physoc.org NEWS AND VIEWS PN 27 that, as previously mentioned, it control of energy stores (Bartness et Lafontan M & Berlan M (1982). is the natriuretic peptides which al. 2009). Characterization of physiological agonist selectivity of human fat cell α2-adrenoceptors: constitute the lipid-mobilizing factor adrenaline is the major stimulant of the α - 1 2 responsible for the exercise-induced Max Lafontan and Vladimir adrenoceptors. Eur J Pharmacol 82, 107–111. lipid mobilization in subcutaneous Stich2 Lafontan M & Langin D (2009). Lipolysis and adipose tissue (Lafontan et al. lipid mobilization in human adipose tissue. 2008). This study is focused on the 1Inserm Unit 858, Institut de Prog Lipid Res 48, 275–297. importance of circulating factors (i.e. Médecine Moléculaire de Rangueil, Lafontan M, Moro C, Berlan M, Crampes adrenaline, insulin and natriuretic BP84225 31432 Toulouse cedex 4, F, Sengenes C & Galitzky J (2008). Control peptides) in the control of exercise- France of lipolysis by natriuretic peptides and cyclic GMP. Trends Endocrinology Metab 19, induced lipid mobilization in human 2Inserm Franco-Czech Laboratory 130–137. subcutaneous adipose tissue. The for Clinical Research on Obesity Moro C, Crampes F, Sengenes C, De sympathetic drive to white adipose and Department of Sport Medicine, Glisezinski I, Galitzky J, Thalamas C, Lafontan tissue differs according to fat M & Berlan M (2004). Atrial natriuretic peptide Third Faculty of Medicine, Charles deposits and so the importance of contributes to physiological control of lipid University, Prague, Czech Republic innervation-mediated effects versus mobilization in humans. FASEB J 18, 908–910. adrenaline effects could produce Sengenes C, Berlan M, De Glisezinski I, References some variability. Nevertheless, Lafontan M & Galitzky J (2000). Natriuretic peptides: a new lipolytic pathway in human coming before the hormonal Bartness TJ, Shrestha YB, Vaughan CH, Schwartz GJ & Song CK (2009). Sensory and adipocytes. FASEB J 14, 1345–1351. hypothesis, both the denervation sympathetic nervous system control of white Stallknecht B, Lorentsen J, Enevoldsen LH, approaches and direct sympathetic adipose tissue lipolysis. Mol Cell Endocrinol Bulow J, Biering-Sorensen F, Galbo H & Kjaer nerve stimulation support a role doi:10.1016/j.mce.2009.08.031 M (2001). Role of the sympathoadrenergic for sympathetic innervation in the de Glisezinski I, Larrouy D, Bajzova M, Koppo system in adipose tissue metabolism during initiation of lipolysis in rodents and K, Polak J, Berlan M, Bulow J, Langin D, exercise in humans. J Physiol 536, 283–294. humans. We must keep in mind that Marques MA, Crampes F, Lafontan M & Stich Stich V, De Glisezinski I, Crampes F, Hejnova V (2009). Adrenaline but not noradrenaline these procedures have a tendency to J, Cottet-Emard JM, Galitzky J, Lafontan M, is a determinant of exercise-induced lipid Riviere D & Berlan M (2000). Activation of α2- affect both sympathetic nerve fibres mobilization in human subcutaneous adipose adrenergic receptors impairs exercise-induced but also sensory fibres present in tissue. J Physiol 587, 3393–3404. lipolysis in SCAT of obese subjects. Am J Physiol the nerves that could interfere in the http://jp.physoc.org/content/587/13/3393.long Regul Integr Comp Physiol 279, R499–R504.
You’ll the power of our cardiovascular systems
If you haven’t experienced the power of ADInstruments cardiovascular systems with PowerLab® data acquisition systems and new generation LabChart® Pro soft ware, here’s three reasons you really should:
Up to 32 channels of data, real time analysis, video capture, automated data extraction, Turbo Research variable recording speeds and unmatched data integrity.
ADInstruments off ers a one-stop shop so you can combine the power of PowerLab data Complete Systems acquisition systems with products by gold standard manufacturers
Our systems are not just powerful, they also deliver an ease of use that boosts productivity. Publish Faster See for yourself at www.adinstruments.com/citations
Contact us for moreinformation: Tel: +44 1865 - 891 623 [email protected] www.adinstruments.com
CELEBRATING OVER 20 YEARS OF INNOVATIONS
Physiology News | No. 78 | Spring 2010 | www.physoc.org Cardio_UK.indd 1 14/1/10 4:40:33 PM 28 PN NEWS AND VIEWS
Work against gravity: in search of the molecular switch for mechano- regulated muscle plasticity Prolonged reductions in weight-bearing muscle activity during bedrest or spaceflight cause dramatic loss in strength due to wasting of postural muscle. Astonishingly little is known concerning the mechano-sensory pathways which underpin this response. Our recent work addresses the process of mechano-transduction by using somatic transgenesis and altered loading to modify the putative mechanoreceptor Work-related stimuli are critical for maintenance of muscle function (Loughna & Goldspink 1990). This Team members from physiological control is apparent the University of Berne, in the dramatic loss of force and University of Pavia and metabolic capacity associated with Manchester Metropolitan reductions in muscle loading during University who contributed real or simulated microgravity, and to the characterisation of the reversal of these deteriorations contractile consequences with subsequent resumption of of FAK overexpression. load-bearing muscle activity. These From left to right, Giuseppe D‘Antona, Roberto Bottinelli responses highlight the instrumental (top), Martin Flück (bottom) role of mechanical factors in the and Stephan Klossner. conditioning of muscle structure and function. In contrast to the accepted clinical importance of this mechano-dependent muscle molecules in cultured muscle suggest that mechano-transduction plasticity and identified mechano- cells (Shyy & Chien, 1997) and the is initiated by strain-induced sensible signalling factors (Nader & architectural coupling of sarcolemma conformational changes in integrins Esser, 2001) there is a distinct lack sites of fibre adhesion (costameres) (Katsumi et al. 2005) and the of understanding of the signalling with sarcomere shortening during subsequent coupling to intracellular mechanisms in vivo. muscle contraction (Pardo et al. signalling (reviewed by Durieux et al. 1983). The functional involvement of 2009). The kinase enzymes involved Focal complexes of proteins have costameres in mechano-transduction in this response have, until lately, not been proposed to convert the and phenotypic control of fully been characterized. mechanical factors of contraction differentiated striated muscle into biochemical signalling inside is largely unexplored. This may Our recent investigation addressed muscle fibres (Fig. 1; Lange 2005; be because integrin receptors this topic by focusing on the Durieux et al. 2009). This idea is which form the adhesive core of role of the integrin-associated based on the association of focal costameres are devoid of enzymatic phosphotransfer enzyme focal adhesions with specific signalling activity. Indirect observations adhesion kinase (FAK; Durieux et
Figure 1. Model outlining the role of costameres in the physical coupling of sarcomere shortening with the sarcolemma and the conversion of contractile forces into biochemical signalling (wavy arrow). For completeness, signalling initiated within the mechano-sensory kinase domain of titin is also indicated.
Physiology News | No. 78 | Spring 2010 | www.physoc.org NEWS AND VIEWS PN 29 al. 2009). In cultured cells, FAK a slow-oxidative phenotype. This possibility was suggested by is involved in mechano-chemical Competition experiments with the the mechano-modulated control of coupling between mechanical combined overexpression of a FAK expression of the gene ontologies for stimulation of integrins and inhibitor (FRNK) demonstrated protein degradation by FAK (Durieux intracellular signal transduction. the specificity of FAK-regulated et al. 2009). Phosphorylation of FAK at tyrosine transcript expression. Probing with residue 397 (Y397) is considered a native, rather than a constitutively The outlined experimental to reflect activation of FAK and active, FAK protein exposed the approach (see Fig. 2) provides an downstream signal transduction post-translational activation of FAK important step forward towards the (Shyy & Chien, 1997). The role of by phosphorylation at tyrosine Y397 investigation of signal integration this signalling molecule in mechano- as a molecular switch of mechano- in a fully developed tissue. The transduction in intact tissue had regulated muscle plasticity (Durieux success of the experiments relied on so far not been investigated owing et al. 2009). the exceptional capacity of muscle to the lethal consequences of FAK for uptake of naked DNA upon inactivation via the germline. Our Our findings compare well electropulsing, and the monitoring study addressed this question with recent findings on the of downstream consequences of using somatic technology which down-regulation of the activation overexpression with a combination allowed overexpression of FAK in status of FAK during muscle disuse of classical and modern fully developed anti-gravitational atrophy in humans (de Boer et al. technologies. We reason that this muscle. The loading state of 2007) and FAK-mediated activation set-up may be of generic interest the muscle was physiologically of the S6Kinase-dependent pathway to muscle research as it offers a modulated in a ground-based (Klossner, 2009). These observations ready, low-cost alternative to labour- model of microgravity (hindlimb indicate that costamere-mediated intensive and expensive transgenic suspension) and muscle loading mechano-transduction is involved approaches via the germline. The (tenotomy; Fig. 2). The monitoring in the anabolic control of muscle electro-assisted muscle transfection of transcriptional, myocellular and mass. It remains to be determined technique also has the benefit contractile consequences pointed to what degree this mechanism is of reducing biological noise by out myofibre transformation with selective for activation of muscle allowing the inclusion of intra- the overexpression of full-length protein synthesis or whether it animal, i.e. contralateral, controls FAK in soleus muscles towards controls protein turnover in general. in paired muscle groups. This advantage was shown in somatic knock-in experiments exposing the hitherto unknown consequences of mechano-regulated extracellular matrix protein expression in muscle repair (Flück et al. 2008). The transfection tool therefore fills a gap for the researcher wishing to explore mechanistic relationships with a tight budget or timeline,or in animal species which do not lend themselves to efficient transgenic modification with germline technology.
Martin Flück Institute for Biomedical Research into Human Movement and Health, Manchester Metropolitan University, UK
References de Boer MD, Selby A, Atherton P, Smith K, Seynnes OR, Maganaris CN, Maffulli N, Movin T, Narici MV & Rennie MJ (2007). The Figure 2. Scheme illustrating the integrative bottom-up approach to investigate the temporal responses of protein synthesis, role of FAK in mechano-dependent muscle regulation. The techniques employed are gene expression and cell signalling in human given in italics and selected results are included. Central to this approach was the quadriceps muscle and patellar tendon to comparison between contralateral soleus muscle pairs of rats being transfected with disuse. J Physiol 585, 241–251. empty plasmid (pCMV) or plasmid for full-length focal adhesion kinase (pCMV‑FAK). Durieux A-C, D’Antona G, Desplanches D, MHC2, combined fast myosin heavy chains; ATP5A1, subunit of complex five of the Freyssenet D, Klossner S, Bottinelli R & Flück respiratory chain. The interested reader is referred to the original article in The Journal M (2009). Focal adhesion kinase is a load- of Physiology (Durieux et al. 2009). dependent governor of the slow contractile
Physiology News | No. 78 | Spring 2010 | www.physoc.org 30 PN NEWS AND VIEWS/LETTERS TO THE EDITOR and oxidative muscle phenotype. J Physiol 587, Dear Sir 3703–3717. Society Noticeboard http://jp.physoc.org/content/587/14/3703.long The article by Launikonis et al. Flück M, Carson JA, Gordon SE, Ziemiecki A & (Physiology News 77, 20) was Scientific Meetings – 2010 Booth FW (1999). Focal adhesion proteins FAK interesting. I took skeletal muscle For a comprehensive overview visit the and paxillin increase in hypertrophied skeletal physiology for undergraduate website muscle. Am J Physiol 277, C152–C162. students for the last couple of years Metabolism & Endocrinology Themed Flück M, Mund SI, Schittny JC, Klossner S, which earned me the nickname of Durieux AC & Giraud MN (2008). Mechano- Meeting ‘muscle man’, though in reality I regulated tenascin-C orchestrates muscle AstraZeneca, Macclesfield, UK, 24–26 repair. Proc Natl Acad Sci U S A 105, 13662– have more fat than muscle. During March 1367. these classes I used to stress that Flück M & Hoppeler H (2003). Molecular calcium release in the skeletal muscle Physiology 2010 – University of basis of skeletal muscle plasticity -- from gene is voltage induced (VICR) and that Manchester to form and function. Rev Physiol Biochem in the cardiac muscle is calcium 30 June to 2 July. Abstract submission Pharmacol 146, 159–216. induced (CICR). However, I used and registration opens on 1 March Katsumi A, Naoe T, Matsushita T, Kaibuchi K & to wonder whether calcium would 2010. Early bird deadline 4 June Schwartz MA (2005). Integrin activation and matrix binding mediate cellular responses to enter the skeletal muscle through Cardiac & Respiratory Physiology mechanical stretch. J Biol Chem 280, 16546– the dihydropyridine receptors in the Themed Meeting 16549. T-tubule. Store-operated calcium University of Birmingham, 1–3 Klossner S, Durieux AC, Freyssenet D & Flueck entry in skeletal muscle has been September M (2009). Mechano-transduction to muscle previously reported (Grimaldi et protein synthesis is modulated by FAK. Eur J al. 2001). The discovery of action Cross Themed Meeting Appl Physiol 106, 389–398. potential-activated calcium current Durham University, 15–17 December Lange S, Xiang F, Yakovenko A, Vihola A, will probably add to a growing list Hackmann P, Rostkova E et al. (2005). The of calcium entry pathways yet to be kinase domain of titin controls muscle gene The Journal of Physiology expression and protein turnover. Science 308, discovered in the skeletal muscle. Symposia 2010 1599–1603. I hope that further research will be done in this area to find the Regulation of neuronal cell volume: Loughna PT, Izumo S, Goldspink G & Nadal- from activation to inhibition to Ginard B (1990). Disuse and passive stretch physiological significance of these degeneration cause rapid alterations in expression of modes of calcium entry in the skeletal developmental and adult contractile protein muscle. 26 April, Experimental Biology 2010, genes in skeletal muscle. Development 109, Anaheim, CA, USA 217–223. Anand Bhaskar Nader GA & Esser KA (2001). Intracellular Neural processes of orientation and signaling specificity in skeletal muscle in Assistant Professor, Department navigation response to different modes of exercise. J Appl of Physiology, Christian Medical 2 July at Physiology 2010, Manchester, Physiol 90, 1936–1942. College, Bagayam, Vellore - 632 002, UK Pardo JV, Siliciano JD & Craig SW (1983). Tamilnadu, India A vinculin-containing cortical lattice in For full details of this, and other skeletal muscle, transverse lattice elements References Symposia visit http://jp.physoc.org (“costameres”) mark sites of attachment Grimaldi M, Atzori M, Ray P & Alkon DL (2001). between myofibrils and sarcolemma. Proc Natl Mobilization of calcium from intracellular Acad Sci U S A 80, 1008–1012. stores, potentiation of neurotransmitter- Non-Society meetings
Shyy JY & Chien S (1997). Role of integrins in induced calcium transients, and capacitative Joint Annual Meeting of the cellular responses to mechanical stress and calcium entry by 4-aminopyridine. J Neurosci Scandinavian and German adhesion. Curr Opin Cell Biol 9, 707–713. 21, 3135–3143. Physiological Societies Copenhagen, 27–30 March Esoteric activities International Workshop – Role of Students hesitating about taking a physiology course may be told it is a mitochondria, ROS and oxidative discipline that can accommodate many talents. Some time ago, during the stress in cellular signalling display of final year (Part II) posters in Cambridge, I asked one of the Natural Hacettepe University, Ankara, Turkey, Scientists what he’d be doing next. He replied that he was going to be a concert 15–17 September pianist. The next I heard of him was as winner of Radio 2’s Young Musician of the Year. Another unexpected talent came to light at the funeral of the late David Interacting with brain oscillations Whitteridge who had held the Chairs of Physiology at Edinburgh and Oxford. Clinical Neurosciences Centre, London The Vicar of St Giles Church in Oxford revealed that he had been an expert on 12 March the romantic novels published by Mills & Boon. Apparently these usually formed a large part of the stock on the Book Stall that David so knowledgably manned at the Church Fête. And on Boxing Day 2009 The Society’s oldest Member, Travel Grants Andrew Huxley, had a new role as one of the judges at the annual inter-pub www.physoc.org/grants Barrel Rolling Race held in Grantchester, outside Cambridge. New international grant schemes: www.physoc.org/international Ann Silver
Physiology News | No. 78 | Spring 2010 | www.physoc.org LETTERS TO THE EDITOR PN 31
On reading the amusing article the idea any more than Mr Darwin. nice if people might pause a little ‘Why I hate epigenetics’ (Physiology He never disagreed with me on and recognize that it is also the News 77, Winter 2009, p. 43) Denis this issue, since neither of us knew bicentenary of my main work, Noble dreamt that he was the Editor anything about the later discoveries Philosophie Zoologique. [DN: see and had received the following of genetics that seemed to exclude note 4] letter, which he then translated into it. He even introduced the idea English for the benefit of readers of of gemmules, particles that he Veuillez accepter, cher Monsieur Physiology News: imagined to flow through the blood l’éditeur, l’expression de mes stream to communicate acquired sentiments les plus distingués, Jardin des Plantes, characteristics to the reproductive Paris, le 21 novembre 2009 organs. Incidentally, your modern Jean-Baptiste Pierre Antoine ideas on micro-chimerism are not so de Monet, Chevalier de la Monsieur l’éditeur far from his idea of gemmules. It isn’t Marck just epigenetics that is resurrecting I had no idea that my scientific the idea of the inheritance of Notes by Denis Noble ideas were to become so politically acquired characteristics, nor would 1. In his introduction to Harvard’s sensitive, though I have been told Mr Darwin be surprised. I have republication in 1964 of The Origin of that the distinguished Edinburgh it on good authority that he was Species, Ernst Mayr wrote (pp. xxv–xxvi) professor of genetics and uncomfortable with the dogmatism “Curiously few evolutionists have noted developmental biology, Conrad of those who usurped his name by that, in addition to natural selection, Waddington, was ignored by his calling themselves neo-darwinists. Darwin admits use and disuse as an fellow American scientists during [DN: see note 2] important evolutionary mechanism. In the McCarthy inquisitions of the this he is perfectly clear. For instance,… mid-20th century because of possible No, the main issue on which Mr on page 137 he says that the reduced association with something called Darwin and I disagreed was whether size of the eyes in moles and other Communism, largely because he there was a direction to evolution, burrowing mammals is ‘probably due to gradual reduction from disuse, but aided invented the term ‘epigenetics’ what I called ‘le Pouvoir de la Vie’. perhaps by natural selection’. In the case and claimed to have shown that it This was not a mystical concept. In of cave animals, when speaking of the confirmed my ideas on inheritance. fact, I thought of it as derivable from loss of eyes he says, ‘I attribute their loss He called those ideas ‘lamarckism’ basic physical principles, and so a wholly to disuse’ (p. 137). On page 455 and was certainly not the first to perfectly natural phenomenon. Some he begins unequivocally, ‘At whatever do so. That damnable giraffe’s of your modern ideas on complexity period of life disuse or selection reduces neck (!) keeps returning to haunt are not far removed from what I an organ…’ The importance he gives me, whereas I thought I would be was thinking. Wouldn’t it be better to use or disuse is indicated by the remembered for having introduced therefore for me to be seen as having frequency with which he invokes this a new scientific subject, which I laid the firm foundations of evidence agent of evolution in the Origin. I find called biology (I was the first to for the transformation of species on references on pages 11, 43, 134, 135, 136, 137, 447, 454, 455, 472, 479, and do so), and for demonstrating the which your Mr Darwin was to build? I 480.” transformation of species and, hence, argued the case for evolution with all the basic truth of evolution. the powerful skeptics of my day. The 2. See Gabriel Dover’s book Dear Mr. highly influential Georges Cuvier [DN: Darwin: Letters on the Evolution of Life and I am deeply puzzled by the term see note 3] ridiculed me mercilessly, Human Nature (Phoenix books, 2001). ‘lamarckism’ for another reason also. even to the extent of gloating over 3. Cuvier argued that the fossil record Your brilliant Honorary Member, my body in its pauper’s grave. The showed sudden, not gradual, changes Charles Darwin, elected to that so-called eulogy that he delivered – an idea that Stephen Jay Gould later position on the foundation of your on my death was described by your espoused in his theory of punctuated equilibrium. Despite the similarity of esteemed Society in 1876, also distinguished evolutionary theorist, his ideas with those of Cuvier, he was espoused the idea that acquired Mr Stephen Jay Gould, as ‘one of characteristics could be inherited shocked by the dismissive tone of the most deprecatory and chillingly Cuvier’s ‘eulogy’ of Lamarck. [DN: see note 1]. In fact, like all partisan biographies I have ever biologists of our time, and even read.’ 4. Philosophie Zoologique is a much earlier, we absorbed this idea from better book than one might imagine, our predecessors. I am amused The fact is that I was reviled and given the low esteem in which Lamarck that an idea for which I was not the died desperately poor (for which is held today. He really did establish the transformation of species and, although inventor should have become so my family had to pay a heavy price) strongly associated with my name. he was not the first to develop the idea precisely because I had established of evolution, he was an indefatigable I may be a ‘demented gloating little the truth of, and argued strongly proponent of the idea at a time when troll’ – in fact, I died so poor that for, the idea of evolution. In this it was even more ridiculed than in they had to throw my body into year of 2009, when you are rightly Darwin’s day – recall that Lamarck died a common lime-pit – but I can’t celebrating the bicentenary of (1829) long before publication of The quite see why I am associated with Mr Darwin’s birth, it would be Origin of Species (1859).
Physiology News | No. 78 | Spring 2010 | www.physoc.org 32 PN MEMORABLE PHYSIOLOGISTS
John Zachary Young – invitation to the dance “Thus there is, in most of JZ’s scientific chief ‘value added’ of an abundant design and output, a tension between working life is his continuous, and his desire to investigate integrative largely successful, insistence on functions of organs and systems as always keeping the whole in mind: a whole and the practical constraint a characteristic he shared with Sir that to do this requires the reduction Charles Sherrington. of a system to an experimentally Andrew Packard (left) and Fabio DeSio manageable and interpretable entity” A difficult balancing act. Often it Memoirs of Fellows of the Royal Society took the form of asking questions the time – to very good use. Indeed, (Boycott, 1998) that he could not answer. In a way, one has the impression that the seed this is also true of the figure of the of the later success of giant axons That a zoologist and former rabbit. with biophysicists lay as much in his professor of Anatomy at University bold portrayal of the system as in College is a natural for a ‘Memorable Young was elected a Member of The the anatomical investigations that physiologist’ article may be Physiological Society in 1932 (then led to it. The emotional engagement glimpsed from a figure illustrating to Honorary membership in 1978). of the scientist in his balancing act James Oschman’s ‘Energy Medicine’ Who was the proposer we wonder between the details and the whole – (Oschman, 2000) (Fig. 1) taken from of this 25-year-old demonstrator the tension of which Boycott writes JZ Young’s Life of Mammals, 1957. in comparative anatomy in whom – is to be found in the drawings. The ‘JZY’ is always tiny: almost microscopic at the posterior tip of the mantle in the much-copied version of 1939 (Fig. 2), same year as the first Hodgkin and Huxley intracellular recordings! Was it modesty, or awe, before the richness uncovered?
Drawing always drawing. Saturday mornings in London were devoted to the microscope: notably to serial sections of whole brains incubated in silver and embedded in paraffin, cut just thick enough to follow main Figure 1 connectives as well as the orientated receptive fields of single neurones – Despite having become head of an many influences combined? He had notably of the octopus. anatomy department in a medical not long returned from occupancy school, Young always considered of the Oxford ‘table’ at the Naples The original of the rabbit in Life himself a biologist, and deliberately Zoological Station – start of a trail of Mammals (see Fig. 3) has every tried to pour biological wisdom into that led to the squid giant axon skeletal muscle–tendon unit the mechanical art of dissecting rediscovery. He was part of a circle numbered and named, represented bodies and naming their parts. His that included Sherrington whose only as a straight line between origin contribution to physiology is by no young co-workers (Denny Brown, and insertion. Whatever the specific means limited to recognizing the then a Rhodes Scholar, being one) intention behind all the effort importance of the giant fibre system were introducing new techniques involved, Young was evidently after of squids, nor to his happy facility into neurophysiology (see Boycott, something that would convey the for grafting germinal ideas from 1998). He put a fondness for drawing dynamic and integrated nature of other fields into his own. Perhaps the – part of the training in zoology at the body. Sadly, neither of the artists in his department at the time, Miss ER Turlington and Miss JID de Vere, is alive to relate its turbulent history. The accompanying text in chapter 8 concerns the mechanical forces acting through the arrangement of struts and ties as the animal moves which “should be at every point proportional Figure 2 to the bending moments … even more
Physiology News | No. 78 | Spring 2010 | www.physoc.org MEMORABLE PHYSIOLOGISTS PN 33
is also an invitation to the dance: an to be few figures ready to make the act of complicity with the student. bolder leap: to use their scientific stature to embrace the implications Oschman shows us where the dance of such ‘fringe’ ideas and work can lead. Duly disregarding the on their incorporation into the numbering on the original, he sees it mainstream1. as a beautiful “tensegrous” network. Young was too much a rationalist2 The hard science of tensegrity has to wish to be called a holist. been in the literature for quite a long time. So have the findings which see “Addiction to holistic concepts … an it extending through the collagenous occupational disease of neuroscientists fascia of the body as a liquid … and of psychologists … is a curable crystalline continuum responsive to a disease from which one recovers by range of physical forces over a range patient therapy with microscopy, of dimensions (see Ho et al. 2006). microanalysis or microelectrodes” (Young, 1975). Figure 3 Even if John Young would have been out of his depth in assessing the Nor would he have wished to be clearly in those hoofed mammals that relation of these forces to molecular tarred by association with Jakob are large and rapidly moving” structure, and agnostic about its von Uexküll. Yet he and the father role in therapeutics, he would have followed rather lamely by of Umweltforschung – author of been pleased to see the figure used ‘Umwelt und Innenwelt’, who is to promote this ultimately simple “There is a danger that such having something of a renaissance comparisons may be accepted idea, and excited by the possibility that proton conduction through the amongst semioticians at the present uncritically … they give only time – had some surprising things suggestions and not exact solutions of tensegrity system integrates the body. It would have coincided with a in common: professional interest in the statics, still less of the dynamics of cephalopods, surgical intervention the vertebrate body”. life-long interest in communication theory and memory. The pity is that, and functional anatomy of the Banal as this instance of Young while inter-disciplinary endeavours octopus brain. Most intimately of pulling himself up short before the have long become the norm in all, both loved Naples, and this was unanswered questions may seem, it biological gatherings, there seem reciprocated. von Uexküll records the remark of a Neapolitan (anxious to make him feel one of them) that he was not a foreigner but a local (Il signore non è un forestiere, il signore è di qua). JZ went one better being awarded honorary citizenship (see left) in 1991 for his long association with the city.
Both Uexküll and Young needed to draw general and philosophical conclusions from their experiments and with it the sense of a duty to communicate these thoughts to others. For the historian, their pursuit of this ‘noblesse oblige’ is no trivial issue. Both biologists took up the task of making scientific knowledge valuable and available to the widest possible audience. Although both of them engaged seriously with what we now call popularization, their principal targets were their respective scientific communities. They were concerned with the elaboration of a new, Deliberation of the Naples City Council conferring Honorary Citizenship on JZ Young improved scientific terminology, – 8/10/1991. ‘per la sagezza e l’umanità tipiche delle migliore tradizioni napoletane’ a way of naming things and their (for wisdom and humanity typical of the best Neapolitan traditions). relations that allowed a steadier
Physiology News | No. 78 | Spring 2010 | www.physoc.org 34 PN MEMORABLE PHYSIOLOGISTS
gained a vast popularity and haunted the Wellcome Institute of the History generations of translators! Young, of Medicine, and from the 53 named from quite different origins fostered skeletal muscles of the rabbit fitted in the thinking of Darwin, wrote in to the regimented routine of his of the brain in terms of coding, heyday in Gower Street. information and programs, etc. gleaned from his association with Fabio DeSio1 and Andrew the pioneers of cybernetics. Packard2 In their emphasis on communication 1Wellcome Centre for the History of as a key to interpreting human Medicine at UCL, London, UK existence and life in general, both 2 Uexküll and Young came close Naples Zoological Station and to present day bio-semioticians Chemin de l’Avelan, La Garde (Kull, 2001). Their main point of Freinet, 83680, France convergence is the importance of Acknowledgements interpretation and meaning for life itself and, subordinately, for the Grateful acknowledgements to JB Messenger and to the Royal Society for free access science of life. For Uexkhüll it was a to publications in celebration of its 350th JZ Young in 1966 – from a pencil and matter of “conformity to the plan”, anniversary. crayon sketch on brown paper by of meaning, of “biological value” References Andrew Packard. rather than “physiological role” (von Uexküll & Kriszat, 1934). Ironically, it Boycott BB (1998). Biographical Memoirs of Fellows of the Royal Society 44, 497–509. progress in the sciences: pointing at is probably easier for contemporary physiologists to accept Young’s Ho M-W, Yu-Ming Z, Haffegee J, Watton A, “what to look for, and where” (Young, Musumeci F, Privitera G, Scordino A & Triglia 1965). almost Whiteheadian statement that A (2006). The liquid crystalline organism and biological water. In Water and the Cell, As a consequence of their strong “living systems can properly be said chap. 10, pp. 219–234, eds Pollack GH, opinions on the place and role of to act in pursuit of certain aims. Each Cameron IL & Wheatley DN. Springer. biology, both Uexküll and Young tries to achieve certain standards Kull K (2001). Jakob von Uexküll: an grew very critical of modern appropriate to its way of life. The result introduction. Semiotica 134, 1–59. physiological language concerned of this continual striving, choosing and Oschman JL (2000). Energy Medicine: the with chains of causal relations deciding, through millions of years, Scientific Basis. Churchill Livingstone. and with ‘mechanical running’. has been a progressive accumulation von Uexküll J & Kriszat G (1934). Streifzüge Young’s opposition to the narrow of information about how best to live” durch die Umwelten von Tieren und Menschen. Ein Bilderbuch unsichtbarer Welten. Berlin aims of physiological reductionism (Young, 1978) Young JZ (1965). The organization of a (concentrating on the cell as than it is for contemporary memory system. Proc R Soc Lond B Biol Sci 163, the proper way to address living evolutionary biologists versed in the 285–320. phenomena) was that it diverted mathematics of selection theory. Young JZ (1975). Sources of Discovery in valuable scientists from the bigger Neuroscience. In The Neurosciences: Paths of and more important questions. This awareness of the importance Discovery, p. 32, eds Warden FG, Swazey J & Commenting on Hodgkin and Adelman G. MIT Press, Cambridge (MA) and of language – interpretation and London. Huxley’s Nobel Prize in Physiology meaning – was expressed in very Young JZ (1977). What squid and octopuses or Medicine – officially ‘for their different ways by the two. Uexküll’s can tell us about brains and memories. Fourty discoveries of ionic mechanisms main aim was to make biology a sixth James Arthur Lecture on the evolution of involved in the nerve cell membrane’ proper and independent science, by the human brain, p. 7. The American Museum – he once half-jokingly said: “To be defining its object against that of of Natural History, New York. unkind, one might say it was like giving the physical sciences. Young sought Young JZ (1978). Preface to Programs of the a Nobel Prize for Literature to people to improve science in general and, Brain. Oxford University Press. who had advanced knowledge of more widely, the understanding typewriters, of ink, or perhaps of radio and power of mankind by refining 1One of the pioneers of conduction in the liquid transmission” (Young, 1977). its language in order to cope crystalline continuum (David Knight, personal adequately with the most important, communication) has supplied us with this example of such global approach: Both scientist/philosopher insisted and most complex, aspects of life. on the relationship between “If injured or ischaemic tissue becomes organism and environment; Uexküll more acidic, information about this could All of which may seem far removed be conducted, analysed and acted on by the devoted much labour to the reform from anatomical description of every continuum”. of biological language, coining a known kind of statocyst amongst 2Young’s lucid account “Why I am a rationalist” number of words (such as Innenwelt, squids and octopuses which for the Rationalist Society, aged 80, is not Umwelt, Funktionskreis), which occupied much of his retirement in listed in bibliographies.
Physiology News | No. 78 | Spring 2010 | www.physoc.org FROM THE ARCHIVES PN 35
AV Hill (1910) being based on the same ideas of function and design.” The possible effects of the aggregation of the molecules of hæmoglobin on its Fletcher persuaded Hill to complete his dissociation curves Mathematics degree before pursuing J Physiol 40 (Suppl), iv–vii new directions. As Hill tells us: This time our look in the Archives turns “In 1907 I took the Mathematical Tripos, to the Proceedings part of The Journal of which in those days was an extraordinary Physiology, and a meeting of The Society business, with fourteen three-hour that took place at King’s College London papers and great public interest as to on January 22nd 1910. The meeting who would be Senior Wrangler [i.e. marks the first one attended, and first achieve the top mark of the year]. It was communication to The Society – one of too much like the Grand National with only three at the meeting! – of AV Hill all its obstacles. I did quite respectably in (1886–1977), Nobel Laureate, doyen of fact, but nobody encouraged me to go British biophysicists, and giant of 20th on with it; which was a very good thing. approaches to drug–receptor century physiology. So I sought Fletcher’s advice again, and interactions, gives a nice account of Hill’s decided soon to become a physiologist.” Hill (christened Archibald Vivian, though December 1909 paper, which derived he disliked both names and was always the Langmuir adsorption equation some In the summer of 1910 Hill published known as ‘AV’) was just twenty-three ten years before Langmuir, and the the first instalment of his scientific life’s at the time. He was working in the January 1910 communication. work on muscle energetics (Hill, 1910). Cambridge Physiological Laboratory, This work was to culminate in the Nobel Hill derived the equations that would having taken his Physiology degree Prize in 1923 – though ‘culminate’ is govern a reversible association between final exams there the previous summer perhaps the wrong word, given that Hill haemoglobin and a ligand, and (1909) and his Mathematics finals two continued to publish papers on muscle compared these to the experimental years earlier. He had published one single energetics in The Journal until the early oxygen dissociation curves measured paper, the previous month (Dec 1909) in 1960s (the last ones, in 1961 and 1962, by Barcroft and others. Hill sets out The Journal. He was not yet a member of with his final PhD student Roger what would subsequently be known The Society (he was not elected until two Woledge). years later, in 1912) and was introduced as the Hill equation, describing the for the King’s meeting by his friend fraction of the macromolecule saturated Though Hill is often associated with Joseph Barcroft. by ligand as a function of the ligand UCL, the institution where he spent concentration. Hill’s equations also took all his later career (after 1923), the Hill’s main scientific interest through into account possible self-association Nobel Committee honoured him for his his career, and the one that was to (multimerization, as we would now say) muscle work carried out in Cambridge earn him the Nobel prize, was heat of haemoglobin. The resulting successive (1909–19) and Manchester (1920–23). During the Manchester years Hill, who production in muscle, and muscle ligand (oxygen) binding events to had been a keen athlete, developed energetics and contraction. However, multiple haemoglobin units give rise to his earliest work on a number of diverse a parallel interest in human exercise what would eventually become known as physiology, and is credited with problems foreshadowed one of his the Hill coefficient. originating the idea of ‘oxygen debt’. wider contributions, the bringing of mathematics and quantitative thinking Colquhoun notes that Hill (presciently?) Hill married into the Keynes academic to physiology. Hill’s protégé Bernard Katz did not attempt to ascribe precise dynasty (his wife Margaret was the sister describes this in his Oxford Dictionary of physical meanings to the parameters in of the economist John Maynard Keynes, National Biography entry on Hill: his equation: and aunt to Professor Richard Keynes). “{Hill’s] first published papers were “My object was rather to see whether an Among Hill’s four children, his son concerned mainly with a theoretical and equation of this type can satisfy all the David or ‘DK’ Hill (1915–2002) followed quantitative analysis of experimental observations, than to base any direct in his father’s footsteps to become a results obtained by himself and his senior physical meaning on [the parameters]”. muscle physiologist, Professor and FRS. colleagues in the Cambridge laboratory. Nicholas Humphrey, Hill’s grandson, has Colquhoun drily adds: “His caveat has They included an analysis of drug action written a touching memoir of helping often been forgotten since then.” in muscle tissue, of the reaction between his grandfather with his experiments as oxygen and haemoglobin, and of the Speaking many years later (Hill, 1969) a child in the early 1960s in a chapter effects of electric stimuli on nerves. about how he had come to take up of the book Curious Minds: How a Child Although Hill later regarded this work as physiology, Hill said: Becomes a Scientist. being of little importance, it contained “A short answer... is, because Walter AV Hill was an early example of a the first mathematical formulation of Morley Fletcher was my tutor at Trinity scientist who engaged in many spheres drug kinetics later generally known [College]...During my first year [at beyond the laboratory, and it would take as the Michaelis–Menten or Langmuir Cambridge] I began to lose interest in a decent-sized book to do justice to even equation. It also introduced the concept some of the things [in mathematics] a selection of his activities. He worked in of co-operativity in complex chemical that to me seemed rather remote from wartime ‘operational’ research in both reactions, signified by a quantity reality and hankered after something World Wars, and was an independent which was widely referred to as the Hill more practical. I realize now that I was MP for Cambridge during the Second coefficient.” much better fitted to engineering than War. He served The Physiological Society David Colquhoun, in an interesting to mathematics, but physiology proved and Royal Society in many capacities, article on the origins of quantitative in the end to be much like engineering, and was an early populariser of science,
Physiology News | No. 78 | Spring 2010 | www.physoc.org 36 PN FROM THE ARCHIVES/UNBELIEVABLE!
giving the 1926 Royal Institution Christmas Lectures. Perhaps the ‘extra- Electronic interference curricular’ activity for which he is most Here is an entry from my diary from remembered is his leading role in the some time last Autumn. I am willing 1930s in the Academic Assistance to bet that almost every academic Council (AAC) which helped Jewish scientist has multiple similar tales. academics flee from the Nazis. Day trip to London for meeting. Hill had used his Thomas Huxley Memorial lecture in November 1933 to On returning home, log on to email denounce the Nazi persecution of the to check what has shown up in the Unfortunately I am teaching when Jewish people, especially of scientists nine hours since I last logged on early it starts and I suspect they will have who had been forced out of Germany. that morning (and sent a few urgent This triggered an extended argument, in messages) prior to toddling off to catch drunk all the free booze by the time I the pages of Nature in early 1934, with the train. (I opted not to pay Virgin get there the German physics Nobelist Johannes Trains ten quid for the privilege of One (1) email from the Senior Stark who had become an enthusiastic wireless internet access on the train so Secretary explaining that we (a Nazi. Stark insisted that Jews were not that I could actually get some reading research group of about 20 academics being persecuted, only people guilty of done for a change. And I refuse to buy and associated staff) will now have “high treason” against the Nazi state. an iPhone). secretarial support from a single Hill’s response was withering: A delightful twenty-one (21) secretary for two hours/week (that’s “With Prof. Stark’s political anti-Semitism emails await my perusal. for all of us – and before you tell me I need not deal... it appears absurd. It is a that is a bit thin, it was previously no fact, in spite of what he says, that many To be precise: hours/week, so things are looking up) Jews or part-Jews have been dismissed from their posts in universities ... No Three (3) pieces of junk email from One (1) email from the Faculty doubt in Germany, after this reply, my suppliers and biochemical and Disability Support Officer telling me: works in the Journal of Physiology and molecular biology reagents (i) I have no students with severe elsewhere will be burned.” One (1) junk email offering to put me disabilities that would mandate special educational provision; and (ii) I have The correspondence famously ended in a directory of important people with Hill commenting, with characteristic one student in a tutorial group this year One (1) junk email from the Univ, dry wit, that since his previous letter he who has a disability, but not a disability had received many donations to help sorry, one ‘In-house University that will require me to do anything the AAC’s cause – but he felt he could communications bulletin’ beyond ‘normal academic practice’. So… that looks like an email telling me not really take the credit, as the donors’ One (1) depressed/depressing bulletin at some length that I don’t have to do generosity surely owed something to from the staff trade union Stark’s (racist-ideological) arguments. anything different from what I always Bernard Katz, himself a Jewish refugee Two (2) inconsequential Faculty do. On the whole that is a plus, though from the Nazis, sought Hill out partly announcements I’m not sure why it meant I needed to because of the correspondence, and be sent the email would later write that the letters One (1) notice about a staff meeting (2 hours minimum duration, judging One (1) email from a colleague “gave me the first glimpse of A.V. reminding me to upload my lecture Hill’s personality…[which] I found… so from experience) that I will avoid if at attractive that I made every effort to go all possible next month to the relevant E-Learning and work with him”. website (or is it a portal?) ‘assuming One (1) email correcting incorrect date the Faculty who we do this teaching Katz also quoted a favourite saying of of said staff meeting for have granted you all access to their Hill’s: “Laughter is the best detergent of site – we’re not sure yet’ nonsense”. Two (2) emails about research seminars I probably won’t have time to One (1) email with actual useful The definitive scientific biographical go to information from a colleague about an source on Hill is Bernard Katz’s ex-student I am writing a reference for monumental Royal Society Biographical One (1) email about a journal editorial Memoir; for a shorter introduction Katz’s meeting next year that I probably And last but not least: DNB entry is a useful starting point. won’t go to as I will be teaching that day. Two (2) automated emails from the Austin Elliott Faculty email server telling me I have One (1) email telling me about Faculty too much stored email. References quota PhD studentships that I won’t be Colquhoun D (2006). Trends Pharmacol Sci 27, able to recruit any students for – even *sigh* 149–157. if I were high enough up the priority Sometimes you really have to wonder Hill AV (1909). J Physiol 39, 361–373. ranking – as I don’t have enough what universities did in the days before Hill AV (1910). J Physiol 40, 389–403. research grant income to ‘cross- subsidise’ a 3-year PhD project email. How on earth did anything ever Hill AV (1969). J Physiol 204, 1–13. get done...? Katz B (1978). Biogr Mem Fellows R Soc 24, One (1) notice about a colleague’s 71–149. retirement do – lucky b*stard. Mark Cain
Physiology News | No. 78 | Spring 2010 | www.physoc.org SOCIETY OF BIOLOGY PN 37
Society of Biology – the first months As most readers will be aware, the Society of Biology formally came into existence on 1 October 2009 following the unification of the Biosciences Federation and the Mark Downs Institute of Biology. Although we plan to build on the heritage of these two undergraduates or postgraduates important bodies, it is important for follow there needs to be the biological science degrees can be all of us to see the Society as a new opportunity to practise science at accredited to give greater confidence organisation with a different outlook the bench or in the field. It is simply to students and employers that they and approach to its organisational not tenable to expand undergraduate provide the solid grounding needed parents. For the first time we have one science education without additional for employment. There is no doubt body to represent the interests of all resource to facilitate hands-on that the topic arouses strong views. The academic community doesn’t biologists in the UK, creating a single experience of designing real want to be forced into a corner with powerful voice to advise and inform experiments and interpreting the no room for innovation in their degree Governments and make a difference. results. As Keith Gull, Professor of programmes or to become a surrogate That aspiration can only be realised if Molecular Biology at Oxford University for technical training programmes, we are a nimble organisation, quick to and Council member of the Society whilst industry bemoans the lack of respond to opportunities, capable of of Biology, said in a recent interview hands-on laboratory skills of many learning from our mistakes and willing to the Standard, responding to graduates. I am convinced there is a to work in partnership. We also need Lord Mandelson’s announcement route to delivery of a solution that to be truly proactive to really drive the on spending cuts, ‘A perfect storm meets the needs of both camps. A policy agenda. is gathering. Our next generation lot rests with the terminology used. of scientists will need to look very Any accreditation programme we At the time of reading this article we carefully at the quality of degrees on will be less than six months old and take forward will benefit from wider offer. If we want top scientists – to consultation and will certainly not there will still be plenty of opportunity innovate, to find out fundamental to shape the way we work. But, to be compulsory. It is likely to focus truths and to get us out of recession on core requirements for biological do that we need to understand what – this is simply not good enough’ matters to our members, how you will science courses to be accredited, such (sic). There has to be the resource as numerical content, experimental judge if we are delivering for you and to properly fund practical biology how best to involve you. Any member design, opportunity for hands-on both in schools and in the higher experimentation and intellectual of the team here would be delighted to education sector. We will be pushing hear your thoughts and, as the newest rigour. It is certainly not about this message at every opportunity, accrediting individuals or asking for recruit, I am particularly keen to learn especially in the run up to the election. about the way The Physiological coverage of specific training tasks or a defined list of techniques. For sure, Society would like to be represented Secondly, the impact of biology, biology is more diverse than chemistry by us. a central theme in the recent or engineering, but by starting in consultation on the Research specific areas real benefit can accrue, The Society of Biology is a single Excellence Framework. Most biologists along with experience. To find out unified voice for biology: accept that the public have a right more visit www.societyofbiology.org • advising Government and to know that the money they spend influencing policy; on research is being spent wisely. Its Finally, we will of course be talking impact on our economy, health care • advancing education and to all the parties in the run up to the system, environment and society is professional development; General Election, forcing them to important to recognise. But it has to focus on their science agenda and • supporting our members; be a sophisticated measurement. We representing the interests of biology, plan to build on existing work and • and engaging and encouraging raising its profile and using our work present a consistent and clear case public interest in the life sciences. on ‘impact’ to argue for investment. around the impact of biology from The Society now has over 70 blue sky research to the most applied. The Society will also be working on Organisational Members and nearly Case studies will be an important part many wider education, science policy 12 000 individual members. This of that and physiology is surely one and public understanding of science represents 80 000 biologists, giving us of the best sources. If you have data issues and, of course, trying to evolve the legitimacy to speak with authority or views to share please email me at new services to benefit our members. in all our work. [email protected] We welcome your suggestions for the Society. Our Council has identified four priority Thirdly, we will continue to work on areas for 2010: a pilot accreditation programme Mark Downs to report back to the Office for Life Firstly, practical biology. No Sciences. The Government has asked Chief Executive, Society of Biology matter which biological discipline us to look at ways in which some (see also article on accreditation on p. 38)
Physiology News | No. 78 | Spring 2010 | www.physoc.org 38 PN SOCIETY
Should The Physiological My personal experience is that riding Manager’ to ‘Outsourcing Manager’ my bike is a lot more risky than any – get the picture? Society accredit lab work I have ever done (and I have university courses? the scars to prove it!). So, if health So is there anything that can be done, or do we just accept that and safety stops practical science at In the good old days when I were scientific training in the UK is the school level, what happens these a lad, studying science meant inevitably downgrading and that days at universities? Well, in addition doing proper experiments. long term we don’t need graduates to H+S, there is the big problem with Chemistry classes at school involved who know how to design and money for practicals – there isn’t concentrated acids, blowing perform experiments? The Office enough of it. Government policy has down Bunsen burner gas tubes, of Life Sciences, set up by Gordon been to increase the number of kids occasional explosions and lots of Brown in January 2009, doesn’t think going to university but it has actively colourful reactions. Most of my so. In its recent ‘Blueprint’ document reduced the resources needed to friends continued this experience (see http://tinyurl.com/n44ema) teach them properly (practical at home and made their own it highlighted the lack of practical subjects now get less supplement fireworks, constructed illegal stills, skills and high level maths in current over classroom subjects than they became amateur glassblowers etc. undergraduate bioscience courses, did). As a result, the practical aspects In biology, we cut sections (using and the implications of this for UK of science in most physiology and razor blades) and viewed them under bioscience. (Now I don’t claim to other bioscience courses have microscopes. We dissected hearts, be any great shakes at maths, but diminished greatly. Few students eyes and even a dogfish and a rat. On I did come out of school knowing do a meaningful final year practical to university we budding scientists about logarithms and making serial project and practical exams are a went, where the practical experience dilutions, and from university with forgotten memory. Of course there continued. Every afternoon we some knowledge of statistical are always library projects which were in the lab stimulating frog analysis and which test to apply and equip you just as well for a life in muscles, contracting pieces of ileum, when.) science (don’t they?). dissecting locusts, examining the The Office for Life Sciences has behaviour of flatworms and so on. So what are the implications of proposed that one thing that We even had practical exams which our risk-aversive society and of a might help improve training is you had to pass to get through government that encourages more accreditation for university courses part one of finals! All the students kids to go to university without that provide a solid practical training had to do a final year practical providing adequate resources to and maths at an appropriate level. project (followed by a viva) and teach them? You probably already Jeremy Ward, Max Headley and I spent many hours trying (and know, the modern bioscience I recently attended a Society of eventually succeeding) to measure graduate, although just as intelligent Biology workshop on this very topic. after-potentials from rabbit superior as their forbears and with probably The workshop revolved around cervical ganglion and investigating a wider theoretical training, cannot the proposal that the SoB would whether they were adrenergic or work in a lab without additional manage an accreditation process cholinergic. My fellow students and training. They also have little idea for bioscience courses that would I went out into the world with a whether they want to do real concentrate on the level and quality background of lab work and a pretty practical science, because they have of practical training and maths clear idea of whether we wanted to no experience of it. Little wonder that the courses provide (see also p. 32). Member societies, such as do more of it or whether we wanted that we now have 4 year PhDs, in The Physiological Society, would to avoid it for evermore. In fact, most which the first is a lab-training year provide the expert assessors for of my friends did go on to become – or that employers won’t consider the accreditation process. The real scientists working in academic, new graduates for scientific roles attendees at the meeting were health service and industry labs. unless they have done a masters with from a number of universities significant practical components or (predominantly the newer ones) and So what has changed? Well, for had an extramural year in industry. included molecular biologists, plant one thing, the emergence of the In fact, many industry employers biologists, geneticists, physiologists dreaded health and safety police. are recruiting PhDs to do what were and pharmacologists. We worked We all accept that it’s important previously regarded as graduate in groups and discussed how to conduct experiments safely, but jobs. The other worrying feature of accreditation might work. It quickly today’s society seems to regard risk our current ‘science training’ is that became apparent that the flaw in as a ‘no go’ area. If you take no risks industry is outsourcing increasingly the accreditation idea is that whilst then life would be tediously boring more of its research to India and most HEIs would like to provide and nothing would ever change. the Far East, where graduates do more lab training, they can’t afford OK, some experiments do involve a get a solid lab training. One of my it. So, most of us concluded pretty degree of risk, but isn’t learning how ex-colleagues from Pfizer has had fast that any accreditation system to manage risk a part of education? his job changed from ‘Recruitment had to be linked to an increase in
Physiology News | No. 78 | Spring 2010 | www.physoc.org REPORTS PN 39
HEFCE funding. SoB will be meeting could be a requirement to receive had led to some remarkable with HEFCE to discuss this issue and the extra funds. We could then start successes in the past, e.g. the let’s hope they get this message producing science graduates who international Antarctic Treaty in the across clearly and forcibly. Some are attractive employees for industry 1960s. This in turn led to monitoring people at the meeting wanted a and government labs and research of the ozone hole and the Montreal stick as well as a funding carrot to students who ‘hit the ground Protocol for tackling its underlying give accreditation ‘teeth’, although running’ in academia. It strikes me causes from pollution. it wasn’t clear what this would that both the students and the be, apart from potential students UK science base would benefit. Alan Thorpe emphasized that voting with their feet. Worryingly, a But maybe I’m just a grumpy and international collaboration is now significant number of the academics deluded old physiologist. seen as being of vital importance by present appeared not to see the the UK Research Councils. The aims need for students to gather data Mike Collis are to promote: UK collaboration from their own experiments but with, and access to, the best foreign thought that analysis of existing Royal Society Seminar – research; the global movement of data was sufficient training for a Science collaboration in a researchers; influencing international scientist. It was also pointed out research agendas; the UK as a that only a small percentage of multi-polar world world centre for research and science graduates go on to do real 21 September 2009 innovation; and tackling global science, the majority using their This seminar, chaired by Lorna social, environmental and other degree as a stepping stone into Casselton FRS, had presentations challenges. Unsurprisingly they have other careers that may or may from Deliang Chen, the new a special focus on Europe and the not be science related. A further Executive Director of the European Research Area. The impact important consideration was International Council for Science of the international strategy is being whether the ‘elite’ universities (ICSU), and Alan Thorpe, the felt in the growth of international would be bothered whether their Chief Executive of the Natural co-authorship, the UK being seen courses were accredited or not, Environment Research Council as the partner of choice in US which reinforces the necessity of (NERC). Chen focussed on structures collaborations, and the high success backing accreditation up with extra for co-operation provided by rates of applications to European resources. ICSU, whereas I found Thorpe’s Framework Programmes. Research presentation particularly striking in Councils UK (RCUK) has now set So is there a viable answer to the illustrating how far the UK Research up offices in key countries, UK problem that we are not providing Councils had moved in supporting Research Offices (UKROs) in Brussels, an adequate training in practical international links, a quite different Washington, China and India, in lab skills and maths for our science state of affairs from when I was order to help UK researchers design graduates? One suggestion (which I working in Polaris House 20 odd and get funding for collaborative first heard from Max Headley) is that years ago, when they mainly seemed programmes (e.g. a focus on there should be an MSci option to focused on the UK scene. Lorna synthetic biology with the National science degrees that would involve emphasized an important driver for Science Foundation, and MRC’s a 4th year. The extra year would this change, in that Governments active collaboration with various provide the practical lab experience now recognize the need to promote foreign agencies on the Global and mathematics that would equip research across international Alliance for Chronic Disease). There its students for a scientific career networks to stay internationally are Memorandums of Understanding and a prerequisite of this approach competitive, and address pressing with various countries, and NERC has was that this should be funded at global problems. a very strong relationship with ICSU an appropriate level. Only a small on e.g. the Inter-Governmental Panel proportion of the more able science Chen gave the background of ICSU on Climate Change. students would take this option, as a non-governmental organisation principally those who are interested founded in 1931 with the aim of There was much support for the in going on to a PhD and those promoting international and inter- concept of promoting international who want to pursue a lab-based disciplinary research, links between space beyond nation state science career. This seems to me science and science policy, and to boundaries, but it was felt that, with to be the most feasible option, speak for the international scientific too many international organizations given the negligible chances that community in UN forums. Over the involved, there were problems Government will provide sufficient next few years they aim to remain in co-ordinating programmes, funding for a proper scientific strategic, create new forums, creating effective structures and training for all science students. Of strengthen their network of regional setting priorities. In particular, the course, this still requires additional offices, and integrate social and UN, UNESCO etc. are too slow and HEFCE funding, but accreditation natural science in tackling issues of consensus driven to have much would then be worthwhile and international concern. This approach effect. The lead is often better taken
Physiology News | No. 78 | Spring 2010 | www.physoc.org 40 PN REPORTS by less bureaucratic organizations, • Increased use of ‘predictive’ genetic development through to the early and organizations with a clearer testing for neurological and psychiatric 20s, so good education is vital at remit and focus such as the Research disorders. all stages for young people, and in Councils. fact people of any age benefit from • Redefining mad and bad and how learning due to the brain’s plasticity. it is treated. The view that you are Liz Bell One research project of interest to all your brain is becoming pervasive, parents of adolescents looked at the Royal Society Policy and has many implications in how offenders may be viewed under the different responses of adolescents Lab – The future in your law. Defending lawyers in criminal and older people to risk taking in brain cases may be saying that it wasn’t driving simulations. The study found the defendant’s fault, his/her brain/ that although both groups were 24 November 2009 genes made them do it. Should people equally careful when on their own, This was a thought-provoking be criminalized for conditions they adolescents were very influenced by debate on some of the social, might not be able to help? Much more negative peer pressure and indulged legal and ethical issues posed by thinking needs to be done as to how in more risk taking with friends. neuroscience evidence should be developments in neuroscience, with Her recommendation of ‘don’t let handled in legal contexts. In terms of presentations from Steven Rose your children drive with their mates’ handling anti-social behaviour, we are sounds sensible. She finished with (Professor of Biology and Director already seeing evidence of problems in of the Brain and Behaviour Research some interesting examples of good the over-diagnosis of attention-deficit and bad explanations for cognitive Group at the Open University) and hyperactivity disorder, with giving effects, all of which then looked Sarah-Jayne Blakemore (Leader children powerful prescription drugs more convincing if even an oblique of the Developmental Cognitive being seen as the norm. Neuroscience Group at UCL). The reference to neuroscience research audience was more diverse than the • Even more worrying is the potential was inserted. This was used to usual mix of scientists, politicians and use of neuroscience for security dangerous effect in some product civil servants, and included people surveillance and military purposes. advertisements. from HM Revenue and Customs, the One company in the USA openly The conclusion of the discussion Financial Services Authority, and the claims that their brain fingerprinting techniques can identify people with was that overall, neuroscience has Serious Organised Crime Agency. I terrorist thoughts and training, made many outstanding discoveries was amused to note none of them and even though there is not much that have revolutionised our was forthcoming about their interests evidence that it works, it has already understanding of the brain, but in the Q&A session at the end! been used in some US courts. The this is being held back by a lack of military have been putting a lot Steven highlighted many radical integration across different levels of of research money into e.g. the advances in neuroscience that were research from molecular to systems. development of new psychoactive We need to get a grip on some of the exciting scientists, philosophers, chemical weapons such as calmatives, health care professionals and even more outlandish claims being made, and transcranial magnetic stimulation and seriously consider the ethical the military with its promises of technologies to directly affect people’s issues of possible future applications. being able to eventually explain, thoughts and moods. mend and manipulate the mind. Neuroscience is increasingly data rich, He described the following major Sarah-Jane then looked at some of but theory hasn’t developed at the ‘promises’ coming from neuroscience the uses and misuses of neuroscience same rate. Brain development, and research: in education. A whole industry how an individual’s sense of self and has grown up around the idea of consciousness come about, are still • New drugs and other treatments influencing the development of enigmas. Finally, as one discussant to restore function, treat neuro- young brains through the promotion noted, there is still a role for good old degenerative diseases, and to protect of products such as Brain Gym, fashioned psychology research. against the development of disease in Baby Einstein etc. Many of these people identified as being at risk are products are based on poorly Liz Bell unlikely to be controversial, even if this understood research, or research involves human–machine interfaces. where the results haven’t been Gareth Roberts Science However, if implants/drugs etc. are then used to enhance the faculties replicated, or completely off the wall Council Lecture pseudoscience. Parents have been of healthy individuals, a whole can 20 October 2009 of worms starts to be opened up. A targeted for such products with the good example is the development idea that the critical period for such The keynote speaker for the lecture of cognitive enhancers to treat development is from 0 to 3 years old, this year was Sir David King, formerly Alzheimer’s; these might end up being and although this is an important the Government’s Chief Scientific used by people who want to enhance phase, it ignores the fact that it was Advisor, and now Director of the their otherwise normal cognitive based on research in monkeys who Smith School of Enterprise and the functions in an analogous fashion to reach sexual maturity at 3 years. The Environment at Oxford University. He how some athletes misuse steroids. human brain continues to undergo gave a rousing description of some
Physiology News | No. 78 | Spring 2010 | www.physoc.org REPORTS PN 41 of the key issues that the world faces, with proper regulatory systems. So what do governments need to and the role of science and scientists In international development, do? They need to put a price on in seeking solutions and influencing King particularly highlighted the behaviours contributing to climate government policy. needs of Africa, which desperately change that we want to turn off, needs science and skills, but and should quickly implement He said that humanity had enjoyed our International Development policies where reductions in carbon some 12 000 years of relatively stable Committee has not addressed this. emissions could be achieved quite temperatures and sea levels, but Human capital development is vital, quickly such as in energy efficiency. global temperatures are now rising particularly in bolstering the higher Governments need to create proper out of control. The good news from education sector. channels of communication with this is that it has probably put paid to scientists to help with avoidance and the planet’s previous periodic ice-age Governments struggle to understand better management of disasters. The oscillations, but changes due to how to use science to protect key to managing population growth global warming could be calamitous. their citizens from disaster. A is education, empowerment and A major contributor to this has been classic example was the Boxing contraception for women. A cultural the explosion in global population Day tsunami of 2004, where paradigm shift is needed in political due to science and technology seismologists had previously and business thinking to respect and successes. Life expectancy has vastly produced a map predicting it, which actively manage the environment. increased, but it takes populations although it couldn’t say when it Resources must not be used faster a couple of generations to adapt by would happen, did show that it than they can be replenished. lowering fecundity. We will need was inevitable. However, when the Solving these problems will require to learn how to manage a global scientists concerned tried to lobby big thinking and an ability to solve population of billions all of whom will governments in the affected region problems in parallel. The good news aspire to a high standard of living. to create an early warning system, is that this has been successfully they couldn’t get anyone to pay them done in some areas such as global There are stark lessons from history any attention, with the results that agreements on CFCs. We need to where civilisations collapsed we have seen. Governments typically collectively build on this to save the from their inability to cope with wait for disasters to happen and only world! climatic change, resource over-use then try to do something about it. and over-population, and we can Liz Bell already see drastic changes in our own world, such as the State of Victoria in Australia, which used to be rich agricultural land and is now beset by drought. Victoria is now Symposium dependent on desalination plants, Regulation of neuronal cell volume : but desalination takes energy, and if this is provided by burning more From activation to inhibition to degeneration Monday 26 April 2010 (15:15 –17:15) carbon, you end up in a destructive Experimental Biology 2010, Anaheim, CA circle of more climate change. Global problems, in climate change, food Chair and Organising Editor Glenn Toney (University of Texas Health production, energy production, Science Center at San Antonio) water management, minerals, Co-chair management of disease and conflict, Sean Stocker (Department of Cellular & all tend to be closely inter-linked. Molecular Physiology, Penn State University For example, policies to use crops College of Medicine) for bio-fuels have contributed to Speakers starvation and a catastrophic rise in Florian Lang (University of Tuebingen, food prices. Some technologies have Germany) Significance of SGK1-dependent transport great potential to help, for example regulation in neuronal volume defense in India where food production Stephen Fisher (University of Michigan, USA) is now threatened by increased Receptor regulation of osmolyte homeostasis in flooding because of climate change, neural cells GM technologies are being used to Eric Delpire (Vanderbilt University Medical develop rice that can survive being Center, Nashville, USA) Kinase regulation of Na-K-2Cl cotransport in submerged for 3 weeks. Rejection of primary afferent neurons GM technologies is something that Glenn Toney (UTHSC at San Antonio) only developed countries can afford, Hyperosmotic activation of CNS sympathetic but we do need to recognise public drive: Implications for cardiovascular disease concerns about it, and governments need to manage such technologies
Physiology News | No. 78 | Spring 2010 | www.physoc.org 42 PN SCIENCE FOR HUMANITY
Science for Humanity Thailand water project: using scientific knowledge to alleviate poverty Tremendous success has been people’s well-being including the water. Whilst the water has achieved in the developed world in reducing their burden of disease and passed the standard test for chemical the fields of science and technology. providing them with an economic content, further improvement is This has increased the standard of advantage. The projects range from needed to improve the bacterial living and the quality of life of those developing a water filtration system content by finding ways to eliminate who are relatively well off. Yet, and a low-cost shelter for disaster harmful bacteria, such as E. coli. unfortunately, poverty still exists in relief to an open source tractor for many areas of the world and many of agricultural use and green charcoal to Science for Humanity is currently the poor are still suffering from lack combat climate change. working with scientists to identify of access to clean water, sufficient solutions that are not only cost energy supply, education and much effective but also culturally more. Something has to be done to acceptable by the community. For reduce the gap between the success instance, chlorine is heavily used of science and the pervasive presence in Western countries to eliminate of poverty in the developing world. bacteria from the water; however, some communities in the Philippines Science for Humanity is an innovative are reluctant to use chlorine due to charity founded by one of the misconception and stigma. Thus, most prominent scientists in the one challenge is to find mechanisms UK, Professor Baroness Susan For instance, under the humanitarian to deliver solutions that are most Greenfield. She founded the charity area of water and sanitation, Science likely to be sustainable. A solution together with Justin Anderson, an IT for Humanity has launched a project to this challenge could provide entrepreneur, and Andrew Doman, called Thailand Water. This project approximately 200 villagers with a former Director of McKinsey. seeks to improve the water quality access to cleaner drinking water, Together they envisioned Science for supplied by a water filtering and reduce the spread of water-borne Humanity to bring about genuine purification system to villagers in diseases, and allow children to go to innovation in science and technology Tha Mai Ruak, Thailand. The current school and adults to work. that can make a real-life difference problem facing these villagers is their to billions of poor people who can access to clean drinking water. The benefit from scientific advances. only water available to them is the Phetchaburi River located near the The strategy of Science for village, which is muddy and dirty, Humanity is to conduct open-source causing the community to experience collaboration using its membership episodes of diarrhea and other water- platform (http://collaborate. borne diseases. scienceforhumanity.net) which is linked from their website A team of students from the (www. scienceforhumanity.net). International School of Bangkok Science for Humanity proactively came together last year to construct matches up seekers and solvers, a water filtration system to supply facilitates collaboration between drinking water to the villagers. The Thailand Water is one of several them, and encourages information existing water filtration system Science for Humanity projects that brokerage. Seekers usually come from is composed of three PVC pipes can meet people’s needs, help to non-governmental organizations containing layers of different sizes alleviate poverty and contribute (NGOs) and poor communities in of gravel and sand, manganese, to sustainable development. If you the developing world. The solvers carbon and ion exchange resin that would like to learn more about our are those with scientific capabilities aid in removing chemicals, rust and existing projects or initiate a science who volunteer to develop solutions unpleasant smells and tastes from and technology-based project that to problems in poor communities. By can aid people in need, please do finding solutions to problems through contact me. I hope that you found the voluntary work of scientists and this article interesting, and that you other solvers, innovation is fostered will get involved with Science for that could make a difference to Humanity. people’s lives. Anu Devi Science for Humanity projects C Uy are science and technology based Science for Humanity that have the potential to improve ([email protected])
Physiology News | No. 78 | Spring 2010 | www.physoc.org ASK A PHYSIOLOGIST! PN 43
Why do I get angry over the smallest because it has allowed medical science Ask a physiologist! things in life? Is there an ‘anger gene’ to correlate disease processes closely In this issue we introduce a new section or something in the brain that triggers with age in humans. On another level, in which sixth form students have been this? (Tomas, age 19) no. As far as I’m aware there isn’t asked to pose physiological questions Professor Laurence Steinberg, Temple anything like tree rings in people, which that are answered by physiologists (or Univeristy, Philadelphia, USA, replies: would allow you to date them precisely occasionally other specialists if they to, say, within a year. However, there Anger is a normal human emotion, are better qualified in a subject). The are things that change as the body experienced by everyone at one time questions in this issue were asked by ages: bones get thinner, muscle bulk or another. Generally we feel anger students at St David’s Catholic College, lessens, teeth wear and fall out, injuries when something we want is blocked by Cardiff. Do you know a teenager with accumulate, as do skin blemishes. We a burning physiological question they something that is out of our control. all notice the effects of these things on would like answered? Ask them to email Although it would be oversimplifying people’s appearance and we are quite us at [email protected] for a chance good at accurately eyeballing someone’s to see their question answered in print. things to say that there is an ‘anger gene’, we know that some people age to within a decade, or even 5 years Patricia de Winter are temperamentally more inclined or so. Doctors tend to distinguish than others to become angry, and it between chronological age – how old Why does your stomach rumble when is likely that this predisposition is at someone actually is – and biological you are hungry? (Alison, age 17) least partly genetic. There is a trait that age – how old they appear to be. This Professor Rod Dimaline, University of psychologists call ‘negative affectivity’ recognises the fact some people age Liverpool, replies: – a cumbersome term for the tendency more quickly than average (especially of some people to be quicker than if they indulge in damaging activities The rumbling sounds are known as others to feel negative emotions (anger, such as smoking, substance misuse or borborygmi, and they actually emanate anxiety, fear, sadness). There are several from the small intestine as well as the excessive alcohol intake), while others studies indicating that teenagers who with the right mix of genes age more stomach. They occur when the gut are high in negative affectivity were slowly. This means that every so often muscles contract and vigorously move similarly prone to negative emotions we get our eyeball estimate wrong and around the contents – food, liquid and as early as infancy. Many scientists have met older people delighted to be especially gas inside the hollow organ believe that adolescents are especially taken for younger than their real age! of the gut. The gas may be present for a susceptible to feeling strong emotions number of reasons such as swallowing – both positive and negative – because of air during eating and drinking, from Although there’s no general method brain systems responsible for regulating for dating people who are alive, there carbonated drinks, or production by our feelings and, more specifically, for gut bacteria. Many people experience may be special instances. For example, modulating emotional reactions, are still it wouldn’t surprise me if there’s a borborygmi, particularly after a meal, developing at this time. when the gut contains the most food, clever physical method of identifying the signature of the Chernobyl nuclear liquid and gas, and when the gut Just because a trait has a genetic accident in people’s tissues, and perhaps muscles are actively mixing and moving component doesn’t mean that it can’t even more accurately in those who were the meal through the stomach and be modified, or even overcome. One undergoing their pubertal growth spurt intestines. However, these sounds are characteristic of individuals who are at the time. usually muted by the food and liquid frequently angry is that they are quick present. to interpret the innocent actions Once people have died, we lose a lot of others in negative terms. When of the clues that allow us to guess During prolonged periods of fasting someone accidentally bumps into them, someone’s age. Carbon dating means between meals, a different pattern of they assume it was deliberate. When that we can tell quite accurately how movement occurs in the gut known as someone forgets to say hello they take long ago a person died. Analysis of the migrating myoelectric (or motor) it as an intentional snub. One strategy tooth wear can provide information, but complex (MMC). This consists of strong for managing anger in these sorts of waves of contraction that start in the situations is to pause before reaching requires assumptions about the diet. stomach and pass right down the gut a judgment about the other person’s Archaeological or forensic estimates of as far as the large intestine (colon), behaviour and see if it is possible to put adult age based on bones tend to be at intervals of about 90 minutes. The it in a different, less negative, light. rather vague – young, middle aged and purpose of the MMC is to sweep any old being about the level of it. Anyone residual food, gut secretions, bacteria Is there a way to precisely detect the who can devise a method of accurately and other debris down the gut towards age of a human body? (Maxine, age 17) assessing a dead person’s chronological the colon in a kind of housekeeping age from their bones will open up a Professor John Lee, Rotheram Hospital exercise in preparation for the next meal. whole new area of research. The sounds made by movement of gas NHS Trust, replies: through the hollow gut resonate much On one level, yes, more precisely than Questions coming in the next issue: more loudly in the absence of much for any other organism. This is because, Why do humans need to sleep? food or liquid. So although the stomach uniquely, you can ask a person for their can ‘rumble’ at any time, the sounds are date of birth, which is one of the first Why have humans lost body hair, as much more noticeable in the absence of things that a doctor will ask, because it is opposed to keeping it as a method of food, when we are likely to be hungry. vital providing a context for interpreting keeping warm? The MMC pattern of activity usually other symptoms and signs that the Where and how is memory stored? ceases on ingestion of further food. patient may have. This is important
Physiology News | No. 78 | Spring 2010 | www.physoc.org 44 PN EDUCATION
Physiology core External Relations Committee. These were then worked on and refined curriculum by the members of the Committee and a number of others; most are Some 18 months ago The Society’s Members of The Society and many External Relations Committee asked are medically qualified. The first draft me to assemble a core curriculum was available in the early summer for the teaching of physiology. The Richard Dyball of 2009 and a second SIG meeting motivation for undertaking this was held in Dublin in July 2009. At arose from disquiet over the closure this meeting the draft document (or merging with other disciplines) was reviewed, some suggestions of their training, have acquired the of physiology departments around for amendments were made and a knowledge and understanding to the UK. An Education Special number of Members agreed to review explain the issues outlined. The Interest Group (SIG) session held and amend specific sections. These currently available document lists at the Cambridge meeting in 2008 have now been incorporated into the all those who have made major confirmed that the members of document that can now be found contributions and is still regarded the External Relations Committee under the Education Resources on The as ‘work in progress’. I would were not alone in this concern. The Society’s website (www.physoc.org/ thus welcome any suggestions for profile of physiology as a discipline corecurriculum.asp). additions and further amendments has undeniably diminished in recent ([email protected]). years. I keyed ‘Department of Since the first draft was placed on Physiology’ into Google and found the website it has attracted many The further development of the only one (unmerged) in England helpful suggestions and many of curriculum has now passed from the on the first page (Liverpool). The the proposed changes have been External Relations Committee to the uncharitable might suggest that incorporated. Perhaps significantly, Education Committee under Louise merging university departments is very few of those who replied to Robson (l.robson@sheffield. ac.uk). tantamount to taking the position the request for suggested changes Contacts have also been made with that ‘now we have SatNav we no felt that too much detail was the Royal Colleges of Physicians and longer need to maintain our road included. A large number felt that Surgeons and it is hoped to share system because if one part fails it is it was unbalanced and I hope that expertise with these and that of the easy to access another route’. the changes made after the Dublin other Royal Colleges (for example the meeting go some way to satisfy those Anaesthetists). All of these bodies As soon as I started to think about who made such comments. are concerned that physiological it, it became obvious that the term understanding (and understanding of physiology covers an extremely Two important criticisms were made other premedical disciplines) should wide range of topics but existing and I have tried to address them be maintained. We hope that as the curriculum guidelines provided in in the current version. The first document matures it will include the UK and Ireland by such bodies as perceived inadequacy was that the links to material on the websites of the General Medical Council do not suggested curriculum ‘dictated what these and other bodies concerned in specify curriculum content. The core should be taught’. This was certainly undergraduate and graduate medical syllabus in physiology was developed not the intention. Rather, the aim is education. We all need to pull in the to give a practical outline of the to allow teachers to compare their same direction to ensure that the level of knowledge that Members of own curricular goals with those of The Society believe is the minimum discipline of physiology maintains their peers. The second important the profile it deserves and that the required by a new medical graduate comment was that if such a document who is about to embark upon a two doctors of the future understand were published it would come to be what they are doing and are safe. year Foundation training. seen as ‘all that medical students It became clear early on that to ever need to know’ and that it would We probably do not need audit or produce a concise document I would stifle new developments or courses targets. Most people are responsible need to reduce the scope in some that are intended to go beyond the and do not want to disappoint their way and since my own involvement basic ‘second MB’ level. Again, this patients, colleagues, managers or in physiology teaching has been for was certainly not the intention. themselves. If we set up targets the most part to medical students, The subject continues to develop in some might be tempted to aim low. our first efforts were directed towards exciting ways as all good teachers We seek to establish a framework of them. Everyone involved recognised, realise. Moreover, the document will understanding upon which excellence however, that students of dentistry, need to be reviewed periodically, the can be built. veterinary medicine and biological suggested date for the next major sciences had overlapping but rather review being September 2010. The Richard Dyball different needs. authors feel strongly, however, that at whatever stage the material is Department of Physiology A list of topics emerged from taught, medical students should, at Development and Neuroscience, brainstorming sessions with the the point of entry to the F1 stage University of Cambridge
Physiology News | No. 78 | Spring 2010 | www.physoc.org EDUCATION PN 45
In vivo pharmacology The experiments carried out are Annual student feedback from the designed to include the acquisition three courses is consistently very and physiology of core skills and understanding as positive. Typically, students identify techniques: acting to follows: the practical elements of the course as both the most challenging aspect increase awareness and • An understanding of how the and the best feature. Students also in vivo models used in the course greatly appreciate the contribution understanding are essential when considered of postgraduate and postdoctoral in relation to complementary With the sequencing of genomes demonstrators – in some cases alternative experimental and the abundance of in vitro data, a postdocs have taken over running approaches. critical challenge in this post-genomic specific aspects of the courses, era is for translational work in whole • An appreciation of the ethical giving them a valuable opportunity animal studies that are pre-requisite issues surrounding the use of to develop their own in vivo teaching to clinical applications. Unfortunately, animals in science. skills. Importantly, all three courses however, there has been a also hold a social event, which allows progressive (and well documented) • An understanding of the students to network informally erosion of the skills base in whole experimental design and statistical and to get to know the staff better animal in vivo experimentation over analysis of results from the animal – especially the postgraduate the last 20 years, resulting in a serious models used. demonstrators to find out more lack of graduates with the necessary about studying for a PhD, particularly • Experience of use of anaesthetics skills to carry out this specialist in research that involves whole animal and surgical techniques, including research. in vivo approaches. cannulation of blood vessels. To help address this important A small sample of student comments: • An awareness of the integration problem the British Pharmacological of responses in vivo and of the level ‘Invaluable insight into the world of in Society (BPS) and The Physiological of concentration and expertise that vivo studies and the different techniques Society joined forces in 2001 to such research requires. involved.’ organise specialist training courses ‘Had much more experience in challenging that enable undergraduate and A key factor underpinning the some postgraduate students in practical methods which is so different to success of the programme has been how I imagined it would be, thus I now the Life Sciences to gain a working the development of a database of have a realistic impression of what in vivo understanding of experimental academic co-ordinators who act as work entails.’ animal in vivo research principles the first point of contact at their and techniques. Three courses are university to notify students of the ‘I gained a much better understanding of run each year – one at King’s College annual call for applicants. Since the what is involved in in vivo work and the London, one at the University of start of the scheme the courses arguments for and against’. Bristol and one at the University of have trained an average of 25 An additional, and very consistent Glasgow. Altogether the scheme students each year from universities message from the feedback costs approximately £60 000 each throughout the UK. Demand each questionnaires is that the students year to run, made possible by grants year for places has grown steadily. greatly value the opportunity to currently from the Wellcome Trust, For example, in 2009 there were 49 obtain practical exposure to in vivo the BBSRC and by donations from applications for a total of 27 places techniques to help determine their industry (notably Pfizer), with available across the three courses, choice of future career. Information additional contingency funding from representing a 14% increase on the from students who have recently the two societies and the Integrative previous year. attended one of the courses supports Pharmacology Fund. Students are selected on a this view – students have reported The in vivo experiments in each of competitive basis, including that the course inspired them to the three courses are tailored to suit an assessment by the Steering go on to postgraduate study that the expertise and facilities of the Committee of CVs and personal involves in vivo work. host institution. However, all three statements of interest. Postgraduates The scheme will be running for its courses cover fundamental principles and postdoctoral research scientists ninth time in 2010 and we look of cardiovascular physiology, with may also apply, but the course is forward to training our next group pharmacological and neuroscience intended primarily for undergraduate of highly motivated and talented components depending on in-house students who are thinking of students. However, funding for the expertise. The courses are run in two pursuing a career in biomedical longer term remains uncertain, and parts – an initial Home Office training research (in academia or industry), new sponsors are needed to ensure module held during the Easter and who would not otherwise have this important training programme vacation, followed in the summer the opportunity to gain experience can continue to help fill the skills gap. vacation by the hands-on practical of in vivo experimental work at their component which runs over 5 days. home university. Richard Apps
Physiology News | No. 78 | Spring 2010 | www.physoc.org 46 PN EDUCATION
A year in industry were without a doubt the shortest and worst netball team in existence At the start of my second year at but we had a brilliant time together. Leeds I decided to apply for an industrial placement to help me As a result of these great friendships, decide whether I wanted to begin both with the other students and my a professional career in science. Up team, I was very sad when I realised until that point I had loved studying that the year was nearly over and I’d physiology but had no idea what soon have to leave GSK and return to I wanted to do with it once that Laura Corns university. It was almost as strange fateful day arrived when I graduated! moving back to university as it was I applied for jobs at numerous starting my industrial year in the companies and successfully landed first place. However, when it came come across before; however, there to starting my final year studies, I a place in the electrophysiology would always be my supervisor or department in the Neurosciences was pleasantly surprised at how the a reliable team member on hand year in industry had affected me, Centres of Excellence for Drug to help. Even though I always had Discovery (CEDD) at GlaxoSmithKline as were the other students who’d support nearby, my supervisor also also taken this year out. We had (GSK). Once I gained the place I gave me a lot of independence, was very excited, but it was also an clearly developed a different attitude allowing me to plan my own days towards our studies compared with extremely daunting prospect. The and decide on the direction in which move didn’t only mean starting the majority of students that had I wanted to take my work. I think progressed straight from second to a job, in which there was a worry this was really important for me as it that I would somehow manage to third year. We had more confidence allowed me to develop my own style in our practical and presentation destroy the lab and possibly the of working. whole building, but it also meant skills and, most strikingly, had a making a completely new group of Although I had a great time during better work ethic. To students that friends in a totally unfamiliar part of my placement there were constant had progressed straight to third year, the country. The prospect became reminders that I was in a corporate managing a 9-to-5 day appeared much less daunting, however, when environment, and one that was not excruciatingly painful, but to us it I realised that there were plenty of particularly flourishing. It felt quite had become the norm. students that were in exactly the difficult at times as I witnessed I would like to think that I would same situation. A couple of months people become aware that their have had a successful third year had before starting the placement, we futures were uncertain while I I not taken a year in industry, but met up at a familiarisation day where knew I was simply leaving in a few in truth I don’t think that I would I found it easy to make friends and months to return to the safety of have reached quite the same level of met my housemates. university. At those times it was academic achievement if it wasn’t important to have the company and for that experience. If I were given On joining the lab at GSK I entered support of the other students; we a small, close-knit team which the choice again I would definitely became a close group, and despite do the year in industry and I would suited me well as they made me the problems at work, we had a heartily recommend it to other feel instantly welcome and I got to fantastic social life throughout the students facing the same choice. know them all quite quickly. They year. Being on a salary, as compared It gave me great practical training, were very pleased with all of the to a student loan, meant that we experience of full time work, the basic lab skills that I possessed. I actually had money to spend and, chance to make useful contacts and, began experimental work within since we had fixed working hours, best of all, made me realise that the first week, and barely left the weekends available in which to working in science is exactly where I lab from that point. This meant spend it. There were guaranteed want to be. that my lab skills rapidly improved, nights out or some sort of social along with my confidence, and event during the weekend. Two of Laura Corns within a month I was happily setting the most memorable times were a Physiology News up my rig each day, patching and paintballing trip, in which my team If you have enjoyed this issue of successfully recording currents. The were thoroughly and deservedly Physiology News please don’t throw it great thing about learning a difficult thrashed (or rather splattered), and away. Put it in your coffee room so that technique like patch clamp, was a long weekend in Stockholm, which others may see it too. that I wasn’t expected to have any was one of the benefits of living We are always looking for interesting previous experience or be able to 10 minutes from Stansted airport. features, meeting reports, news solve instantly any problems that The most fun I had throughout the items and photographs. Contact The occurred. As all electrophysiologists year, however, was the time I spent Physiological Society Publications Office will know, there were always new with the rest of the girls in the ([email protected]) with your problems cropping up that I had not netball team that we formed; we suggestions.
Physiology News | No. 78 | Spring 2010 | www.physoc.org EDUCATION PN 47
Cardiff University (theoretically) directly proportional groups and creating a Facebook to the number of students. Sadly, this page also helped raise our society’s Physiological Society formula seems to be flawed when head above the parapets. However, faced with physiology students. We once we had an interested group of Whilst contemplating the fruit content have learnt our lesson for the next students, the delicate issue of money of a Christmas pudding and convincing careers evening scheduled early in came about. To help raise funds we themselves that it really could count as 2010, which we hope will attract have asked for an annual fee of £2. one of their ‘five-a-day’, a group of final even more students eager to find out So far this money has helped pay year physiology students at a Christmas where their physiology degree can for advertising material and the party in 2008 decided to set up the take them. all-important food we have previously Cardiff University Physiological Society. mentioned. We feel that this fee Now in its second year as a society, is fantastic value, and also helps outgoing President Stuart Hanmer, and us get discounted rates for society incoming President James Selvey discuss merchandise such as hoodies, which the activities of the society, and give we hope to be sporting before the their hopes for the future. summer. Our main motivation for forming The Cardiff University Physiological Momentum is important in setting the Cardiff University Physiological up any kind of society. After the initial Society (CUPS) was to bring together Society logo, complete with (artistically licenced) action potential. excitement of getting members and all physiologists and other students hosting a successful event, the onus studying physiology (including On the social side, the once-annual is on ensuring that this enthusiasm biomedical scientists, anatomists physiology Christmas meal for is maintained throughout the year, and intercalating medical students) students and staff has been re-kindled and continues on into future years. in Cardiff University’s School of by CUPS and has so far been a great Thankfully, this has not been a Biosciences. Students find the success. Our most recent meal also problem for CUPS. The ability to modular nature of the biosciences welcomed Ole Petersen FRS, who shape their own society, especially schemes at the university good takes on his new role as Director of one founded so recently, has proved from an academic point of view, the School of Biosciences early in an enticing prospect for physiology especially in terms of giving a wide 2010. We are now hoping to establish knowledge base in the first year, but students. After all, being involved a summer ball in the Cardiff School socially they can be a nightmare! The in something new is always more of Biosciences. This should be a smallest lectures still have hundreds exciting than rehashing the old – fantastic opportunity for students to of students from a wide range of that’s why, as they so diplomatically get to know each other outside of the degree schemes, so it can be difficult say, they picked physiology over lecture theatre. to meet people: it’s a ‘water, water, history. everywhere’ scenario. The Physiological Society proper So what does the future hold for was helpful in establishing our One of the primary aims of CUPS is CUPS? We hope that as the society student society. Early in 2009, to work on the social side and get becomes more well known in the Irrum Magre, who was then The physiologists meeting each other in School of Biosciences that we can Physiological Society’s Membership the first year, so as not to be surprised expand our numbers and help and Education Co-ordinator, very to find that other people study students, should they so wish, get kindly came to speak to us and give physiology too. Variety is the spice an idea of what physiology might us an idea of what the Physoc could of life, and through a combination of offer as a career. However, we do offer us in terms of support. As we careers sessions and the obligatory not want to restrict ourselves to continue to find our feet, we aim to fancy dress-based socials, we think undergraduates. Postgraduate form closer associations with The we are achieving this. One of the students will also benefit from what Physiological Society, providing highlights of the society’s first we have to offer as a society, and undergraduates with the opportunity year was our Biomedical Sciences we hope that we can provide help to visit conferences and get involved Careers Evening. We aimed to have to them, also. Charity work is also with physiology outside of Cardiff a selection of speakers representing an area which we would like to get University (see p. 48). a range of different disciplines, involved in, as is promoting the study both clinical and academic. To As with any new idea, there are of physiology in local schools. As Niels this end, we invited a dietician, a bound to be difficulties in the Bohr once said, ‘Prediction is very PhD student and a trainee clinical beginning. We have been fortunate difficult, especially about the future’. haematologist. This event was a great in that these have been relatively few This is certainly true, but we have a success, with around 60 students and far between. The initial problem very good idea about what we would attending, all eager to ask as many of gathering together physiologists like to be doing. questions as possible as the thought is easily solved through speaking to of exams loomed. As with any large staff who have regular contact with Stuart Hanmer and James event, the requirement for pizza is students. Sending out emails to year Selvey
Physiology News | No. 78 | Spring 2010 | www.physoc.org 48 PN EDUCATION
The resounding success of a new undergraduate initiative On 14th November 2009, Keble College, Oxford hosted the first Undergraduate Physiological Sciences Conference (UPSC) – a one-day event organised by and designed especially for undergraduate physiologists.
The first UPSC welcomed over 130 undergraduates from 34 different universities across the UK and Ireland. Welcoming talks by Ania Szmuksta, lead organiser, and Michael Collis, Chief Executive of The Physiological Society, were followed by rousing and enlightening keynote lectures by Denis Noble CBE The organising committee (from the left): Lauren Parker, Chloe Lim, Ania Szmuksta, FRS and Julian Paton. The students Claire Machin and Charlotte Whicher. also attended careers sessions for which Mary Morrell, in collaboration of the NADPH oxidase isoform The post-conference materials with the Oxford Careers Service, Nox4 in cells of the cardiovascular including the photo gallery, the presented an excellent CV system.’ The abstracts submitted abstract book and the slides from workshop and Clare McVicker of the by the undergraduates were also the presented sessions, are now Wellcome Trust, Daniel Rosen and used to select one student to available to download from the UPSC Daniel Kumpik, graduate Oxford present a short prize talk. This was website: scientists, drew attention to the awarded to Anna Graca from the many options that await those www.ouphysoc.co.uk/upsc2009 University of Aberdeen, who spoke considering doctoral research. The on ‘PLD-coupled mGluRs modulation Ania Szmuksta conference also attracted several of synaptic-like vesicle recycling senior scientists from the Oxford (Lead organiser) and afferent discharge frequency in academic scene and beyond, who mouse mechanosensory terminals.’ joined the undergraduates for the The evening was rounded off by a Undergraduate membership poster session and for the careers dinner at Freud’s restaurant, with and networking evening. The Society supports many delegates choosing to stay on Undergraduate Members by and explore the Oxford nightlife. One of the highlights of the day was offering the following benefits: the student poster session for which Student feedback revealed a very over 50 entries were received. The positive reception of the meeting • Free attendance at Society panel of judges commented on the with nearly 90% of the respondents meetings high standard of the posters, and expressing interest in attending considered most to be comparable • Travel grants future UPSCs. The attendees not to those presented at professional only complimented the contribution specialist meetings. The first poster • Funding to host a seminar of invited speakers, but also the prize was awarded to Nishanthan performance of the undergraduate • Techniques Workshops Manickavasagar from King’s College organisers; indeed Professor Noble London for ‘Subcellular localisation considered the meeting went as • Opportunity to apply to host smoothly as similar events run by an Undergraduate Conference ‘professionals’. • Networking opportunities
The organising committee would • Hard-copy of Physiology News like to thank The Physiological Society, the British Society for Applicants must be studying for a Neuroendocrinology, the University degree in physiology (or a related of Oxford and Peprotech for their subject). generous financial support, with An Oxford physiologist, David Thomson, special thanks to Chrissy Stokes at The Physiological Society for her For more information, please email talking to Denis Noble at the Natural [email protected] History Museum. invaluable help.
Physiology News | No. 78 | Spring 2010 | www.physoc.org EDUCATION PN 49
Exercise physiology sixth form workshop respiratory volumes change (but not the overall capacity) with exercise, The Department of Biomolecular requiringMeasurement theof resting students to exercise on respiratory volumes using the and Sport Sciences at Coventry thespirometer. cycle ergometers. University hosted a workshop aimed at students studying exercise Feedback from the students and physiology as part of their ‘A’ level teachers was very positive; this was or BTEC National Diploma studies. very pleasing to hear after all the The workshop was designed to hard work that went into organising excite and inspire these students and delivering the day. A big thank so that they may consider a career you to everyone involved, to Angela in exercise physiology or a related Breslin from The Physiological area. Content included the effects Society, and to The Physiological of exercise on the respiratory Society for sponsoring the event. system, the physiology of jumping, Jayne Hastings and the Douglas bag technique Measurement of resting respiratory AssociateMeasurement Head of respiratory (Development) to determine oxygen uptake and volumes using the spirometer. volumes at rest using the energy expenditure. Laboratory Departmentspirometer. of Biomolecular and DeterminationSport Sciences, of jump height Coventry using the jump University activities were designed to be very mat. ‘hands-on’ and allowed the students The outreach grant scheme is to use equipment they would not open to all Members and Affiliates normally have access to in their of The Society who would like to school/college. communicate the excitement of The workshop began with an physiology to young scientists and introductory talk on further study the wider community. For more and career opportunities involving information, please visit our website exercise physiology. Students were or email [email protected] then divided into three groups to rotate around three laboratory sessions. Get involved and The oxygen uptake and energy write an article for expenditure lab session was taught by Mike Price. Students used Douglas Physiology News bags to collect expired air at rest Have you done something in (5 minute collections) in order to Determination of jump height using teh your studies you would like to calculate resting oxygen uptake and jump mat. Determination of leg (and lower back) strengthrecommend to see if it is a determinant to other of jump young energy expenditure. Each student height. had the opportunity to analyse their The physiology of jumping scientists, attended an amazing own Douglas bags using gas analysis performance was taught by Rob training course or got an issue equipment – something that schools James. In this session, the students you’d like to get off your chest? do not usually have available. measured their vertical jump height If you enjoy writing then why not using a jump mat to investigate contribute to Physiology News. We On your bike! Investigating factors that could determine jumpthe effect ofhave exercise an annualon prize of £200 for performance, length and strengthrespiratory volumes.the best published article written of their leg, and also their hand-grip by an Affiliate or young scientist. strength. Data from the entire class If that isn’t enough incentive, showed that those who had the contributing to the magazine is a longest legs, the strongest legs and great extra on your CV and a nice were generally strong overall (as way to tell a broader audience indicated by hand-grip strength), about the things you do. We had the highest jump performance. are always looking for people to The lab session investigating contribute to the Affiliate pages in respiratory volumes was taught the magazine and would love to by Sadie Dean. The aim of this hear from anyone who would like session was to investigate the to get involved. different respiratory volumes that Email us for more information or can be measured in lung function to discuss ideas at: On your bike! Investigating the effect of testing using spirometers and peak flow meters. It also looked at how [email protected] exercise on respiratory volumes.
Physiology News | No. 78 | Spring 2010 | www.physoc.org Determination of oxygen uptake and energy expenditure at rest using the Douglas Bag technique.
The outreach grant scheme is open to all Members and Affiliates of The Society who would like to communicate the excitement of physiology to young scientists and the wider community. For more information, please visit our website or email [email protected].
50 PN EDUCATION
Young Physiologists’ Symposium by four talks by young physiologists. After a coffee break, the Ion Channels 23–24 September, Leicester. Ion channels and receptors in cell physiology in Neuroscience session started with David Brown (UCL) who delivered a great talk, full of first-rate science and funny to boot. Four more talks by early-career scientists followed and brought to an end the Leicester Young Physiologists’ Symposium.
The prize for the best talk was given to Matt Barker (University of Leicester) for his talk ‘Vestibular projections to the dorsal cochlear nucleus are characterised by the vesticular glutamate transporter Symposium photo on the lawns of Stamford Hall. Sitting on the bench from left to VGLUT-2’. There were two winners right: Noel Davies, Martyn Mahaut-Smith, Steve Watson, John Challiss, Ian Forsythe, David Brown and standing on the right John Mitcheson. for the poster prize: Chunjing Gu (University of Cambridge) and Rubia The late summer’s sun pouring across five rounds, the teams were locked Araujo (University of Nottingham). the perfectly manicured lawns of in a battle of trivia. Although there I would like to thank the staff in the Stamford Hall at the University of was only one winning team, a good Department of Cell Physiology and Leicester and the tranquil nature of time was had by all. Alongside the Pharmacology, particularly Jacqui the registration desk masked the quiz there was a magician on hand Noon, Alan Willcocks, Blair Grubb and shear panic that lay in my chest. After to dazzle and wow the crowds with John Mitcheson. Thanks also go to the a year of planning, and with over 120 close-up tricks. guest speakers and, of course, the rest people registered, I was wondering if anyone would turn up? As Kevin Day two began with Steve Watson of the organising committee. (Birmingham University) giving his Costner found out in Field of Dreams plenary talk in the Cardiovascular Steve Thomson – if you build it, they will come. Sure Receptors session, which was followed University of Leicester enough, by the time the welcome address was due to start we had a full house. Leicester’s own John Challiss kicked Discover more... things off with an insightful talk on glutamate receptors. There then followed four good talks by young physiologists to complete the Receptors in Neuroscience session. The second session, Cardiovascular Ion Channels was opened by Godfrey Smith (University of Glasgow). As ever, he presented high-level science ...explore boundaries in a manner that held everyone’s you thought impossible with other systems interest. The rest of the session was In thousands of laboratories worldwide, our user-friendly taken up by four talks from PhD Spike2 and Signal software, together with CED1401 hardware students and post-docs. deliver power and flexibility to fulfil the needs of researchers now and in the future.
The poster session and drinks CED has nearly forty years’ experience producing high-speed reception was a lively affair, which data acquisition & analysis systems. Our customer support is unrivalled; we offer free software and hardware help desks got livelier as more wine and Pimm’s and a three-year warranty on all new 1401 interfaces. were consumed. Lots of people were Start exploring... debating the merits or otherwise of Import your data into our software. Visit www.ced.co.uk today, different techniques and approaches. or contact us for a hands-on demonstration at [email protected] The symposium dinner followed the poster session. Over the four courses of dinner there were more conversations and some joke telling. CED www.ced.co.uk Cambridge Electronic Design Limited After dinner everyone retired to the Science Park, Milton Road, Cambridge CB4 0FE, UK. Telephone: (01223) 420186 bar where the hardest test of the day Email: [email protected] USA/Canada Toll Free: 1 800 345 7794 Web: www.ced.co.uk was to take place: the pub quiz. Over
Physiology News | No. 78 | Spring 2010 | www.physoc.org AFFILIATE NEWS PN 51
Industrial experience – a view my research from a wider angle as a small part in a much larger picture. stepping-stone on the pathway to career success? Industry projects are often multi disciplinary and this team-based Research in physiology can be tough approach means that projects move and is highly competitive. To be an more quickly and with much more effective and successful researcher interaction with others than is often Sam Passey requires a huge range of skills, including seen in academic labs. The collaborative both the intellect and practical team-based environment helps to aptitude to undertake the research develop people management and itself and also related skills required good communication skills, essential At the end of such a scheme, usually for communicating and publishing for those wanting to progress to 3 years, postdocs have the choice of your work, collaborating with other become group leaders. There are also returning to academia taking with them researchers and managing your projects opportunities to gain specific scientific the valuable industrial experience they to a successful conclusion. Whilst many expertise through industrial experience, have gained, or seeking employment in of these skills can and often are learned including access to cutting-edge an industrial setting with the benefit of during the training undertaken for a equipment, exposure to new techniques already having 3 years of solid industrial PhD and in postdoctoral work, there is and the chance to undertake additional experience under their belts. much to be said for gaining experience training courses to develop specific and skills from a range of different additional skills. If you don’t want to leave your research environments in order to current position but are curious achieve more balance in your skillset. So, how to gain experience in an about life in industry, there may still industrial research setting? For under be opportunities to link to industry As I prepared to write this article, I was graduate and PhD students, there are and perhaps gain some experience also planning my next career move as a number of opportunities such as there. Does your research offer any part of a relocation plan to London or sandwich or summer placements and commercial benefit that you could the South East. When assessing my the CASE PhD studentships that are develop further with a suitable future options, I also considered my partially funded by an industry partner industrial partner? Does your own experiences during my degree, and allow students to spend time supervisor or any colleagues have PhD and postdoctoral career and the working in the partner company during existing industry contacts in a relevant advantages I have gained from these their PhD. field that might be used to set up a experiences. As a researcher who short-term placement in the company has spent time working in a range of At the postdoctoral level there are a or some collaborative research? Many academic and industrial labs at large number of fellowship opportunities, universities now have ‘knowledge and small institutions and companies, such as the Royal Society Industry transfer’ departments that specialise what struck me most was how the time Fellowship (www.royalsociety.org), in managing and developing links I had spent in industry had helped to that are specifically designed to allow between academia and industry, so shape my research attitudes and ideas, an academic scientist to work on a these may provide a useful starting and helped me to develop skills that are collaborative project with an industrial point for those interested in making benefitting me today, despite making partner, gaining valuable industrial new links with industry. a move back into an academic research experience and making industry position. connections that can live on even Of course, there are downsides that after the fellow returns to their home one must consider about research in Research in the pharmaceutical industry institution. industry; for example, opportunities to is very disease-focused and as such, publish primary research papers may be experts with specific knowledge in A number of the big pharma or restricted depending on the research the underlying physiology and related biotech companies are now offering field and the company involved, laboratory techniques are often sought fellowship schemes aimed at recruiting and issues regarding confidentiality for research programmes in specific postdoctoral researchers; for example, and intellectual property that some disease areas including cardiovascular, Novartis, Genentech and Millenium people may find difficult. In addition, musculoskeletal, neurological, Pharmaceuticals all offer postdoctoral there may be less freedom to pursue respiratory and gastrointestinal fellowship programmes. Such schemes interesting lines of investigation if they disorders which represent major often involve dual mentorship from do not fit directly within the remit of research efforts for many of the academic and industry advisors, and the research programme. However, for big pharma companies. For many are intended to contain a significant those looking to apply their physiology physiology researchers, having this portion of preclinical basic research. skills and contribute to a larger research immediate disease relevance provides Postdocs on such schemes experience programme with more immediate an important driving force for their life in industry and have access to the physiological relevance to actual work. From a personal perspective, the funds and equipment that industry patients, even a short spell of research goal-led approach to research projects offers whilst still pursuing an academic- in a pharmaceutical or biotech company that I have encountered in industry has linked project. Fellows are expected to may enhance their skillset and who allowed me to develop a more focused publish in peer-reviewed journals and knows – it may even pave the way to approach to my own research work. present data at scientific meetings in new and exciting career opportunities. Industry has shown me the other end of exactly the same way as they would the research spectrum, allowing me to expect to if working in an academic lab. Sam Passey
Physiology News | No. 78 | Spring 2010 | www.physoc.org 52 PN THE SOCIETY’S JOURNALS
relationships between the cellular and extracellular structure of cardiac muscle and the electrical and mechanical function of the whole heart during ventricular remodelling, the University of California San New Editors for and arrhythmia. Dr McCulloch is a Diego, where he joined the faculty PI on the NCRR-supported National Experimental Physiology in 1987. He is a member of the Biomedical Computation Resource, UCSD Institute for Engineering in in 2010 and has grants from the NHLBI, Medicine, the California Institute for NSF and UC Discovery on cardiac Telecommunications and Information tissue engineering, ventricular Technology, a Senior Fellow of biomechanics, signalling pathways the San Diego Supercomputer in cardiac hypertrophy and Center, and a member of the failure, cardiac electromechanical UCSD Center for Research on interactions, and computational Marc Kaufman Biological Systems. Dr McCulloch cardiac biology. is a Principal Investigator of the National Biomedical Computation Resource and Co-Director of the Marc received his PhD in Cardiac Biomedical Science and Physiological Psychology in Engineering Center at UCSD. 1977 from the University Miami. He served as Vice Chair of the He spent the next three years Bioengineering Department from as a postdoctoral fellow in the 2002 to 2005 and Chair from 2005 Cardiovascular Research Institute to 2008. Dr McCulloch is Director Gregg Semenza at the University of California San of the HHMI-NIBIB Interfaces Francisco working in the laboratory Graduate Training Program of Hazel and John Coleridge. His first and the accompanying UCSD faculty position was at the University Interdisciplinary PhD Specialization Dr Semenza received undergraduate of Texas Southwestern Medical in Multi-scale Biology. training in Biology at Harvard Center where he investigated neural College; MD and PhD degrees from control of the circulation during Dr McCulloch was educated at the University of Pennsylvania; exercise under the mentorship of the University of Auckland, New pediatrics residency training at Jere H Mitchell. Currently, Marc is Zealand in Engineering Science Duke University; and postdoctoral the Research Associate Director and Physiology receiving his PhD in training in Medical Genetics at the of the Penn State Heart and 1986. He was an NSF Presidential Johns Hopkins University School of Vascular Institute in Hershey, PA, Young Investigator and is a Fellow of Medicine, where he has spent his USA. His research focuses on the the American Institute for Medical entire career. He is currently the exercise pressor reflex which arises and Biological Engineering. He has C. Michael Armstrong Professor at from contracting skeletal muscle served on the Board of Directors Johns Hopkins with appointments and which functions to increase of the Bio-Medical Engineering in Pediatrics, Medicine, Oncology, sympathetic discharge to multiple Society, and is currently Associate Radiation Oncology, Biological vascular beds. Particular attention Editor of the Medical and Biological Chemistry, and the Institute of is paid to the mechanical and Engineering and Computing and PLoS Medical Genetics. Since 2003 he metabolic stimuli arising in both Computational Biology and co-Editor- has served as founding Director health and disease that activate in-Chief of Drug Discovery Today: of the Vascular Program in the the thin fibre muscle afferents Disease Models. He is on the editorial Johns Hopkins Institute for Cell comprising the sensory arm of the boards of the American Journal of Engineering. Dr Semenza’s reflex. Physiology: Heart and Circulatory laboratory identified hypoxia- Physiology and Computer Methods inducible factor 1 (HIF-1), a protein in Biomechanics and Biomedical that allows cells to respond to Engineering and Cellular and Molecular changes in oxygen availability. The purification of HIF-1 in 1995 Andrew Bioengineering. Recently, he has opened the field of oxygen McCulloch given the Konrad Witzig Memorial Lecture and the Donald Wassenberg biology to molecular analysis Memorial Lecture. and has revealed major roles for HIF-1 in many developmental, Andrew McCulloch is Professor Dr McCulloch’s lab uses physiological and pathological of Bioengineering and Jacobs experimental and computational processes. In collaboration with the School Distinguished Scholar at models to investigate the laboratory of Nanduri Prabhakar,
Physiology News | No. 78 | Spring 2010 | www.physoc.org THE SOCIETY’S JOURNALS PN 53 the critical role of HIF-1 in oxygen science and education project in sensing by the carotid body has Guangdong Province, the national been demonstrated and linked outstanding young experts in to the pathogenesis of systemic Chinese and Western integrative hypertension in response to chronic medicine, the title of Glaxo Award intermittent hypoxia. Dr Semenza for outstanding young doctors, the serves on the editorial boards of Ten Outstanding Young Persons in Antioxidants and Redox Signaling, Guangdong Province Nomination Cancer Research, Cardiovascular Award, the State Department Research, Circulation Research, Journal experts in special government of Clinical Investigation, Molecular allowances, and the Guangdong and Cellular Biology, Molecular Cancer provincial authorities forefront Therapeutics, and Oncogene. He positions. is Editor-in-Chief of the Journal of Molecular Medicine. He has been Experimental Physiology elected to the Society for Pediatric Winter Games Themed Issue Research, American Society for Clinical Investigation, Association The March issue of Experimental of American Physicians, and the Physiology (published in February) National Academy of Sciences, USA. contains a series of articles that provide an insight into elite human performance in the unique, and turn with the aim of identifying often spectacular, environments limiting factors to performance. Our associated with the Winter Olympics. intention, therefore, was to invite submissions from those with a novel, When most people think about insightful and most importantly, these Games we conjure up Xi-Yong Yu integrative, view of the limitations glorious images of snow and high to performance in Winter Olympic mountains; but when physiologists sport. We are delighted with the think of cold and altitude, most unique collection of articles, clearly immediately think of environmental demonstrating that the physiology Professor Yu engages in the research challenges including hypothermia of a medal-winning performance in field of molecular cardiology and and hypoxia. We have encouraged many winter sports is still far from pathophysiology. His main research review authors to resist stereotypical fully understood. interests include chronic heart thought progression and avoid failure and diabetic cardiomyopathy the standard, and perhaps dated, If one examines skiing and skating, comprising three research aspects: tactic of examining each of the a fall is always possible, but the (1) gene therapy and stem cell major physiological systems in important question is whether therapy in heart repair; (2) the role of pro-inflammatory cytokines in Sir Ranulph Fiennes expresses his support for the the development of cardiovascular Experimental Physiology 2010 Winter Games Themed issue disease; (3) epigenetics and I am very pleased to see this collection of articles that contain so much pharmacogenomics in cardiology. excellent information about an area that has long interested me, that of He has published more than 300 how we humans can perform so well under extreme conditions, resulting papers in academic journals at home from either physical exertions and/or environmental stress. This timely and abroad, published 7 books, issue of Experimental Physiology explores the current understanding of and received 6 National invention how our bodies react when internal and external challenges are combined, patents. He has undertaken more and provides a fascinating insight into how finely tuned our responses than 20 research projects from must be to achieve our set goals whether as athletes or explorers. Whilst the National Natural Science it is surprising to me how much we do already know, these papers also Foundation, the Provincial Natural identify where our knowledge is inadequate to allow a full mechanistic Science Fund and other scientific and explanation and indeed how much more research needs to be done. technological programs. Professor However, it is particularly gratifying to see how information from different Yu won 5 Medical and Health disciplines is being harnessed to this end. Progress Awards, and 3 Science and Technology Awards from Guangdong Provincial Government. He has also been awarded one of the academic and technology leaders of medical
Physiology News | No. 78 | Spring 2010 | www.physoc.org 54 PN THE SOCIETY’S JOURNALS or not the fall was preventable. inactive muscles (Bill Sheel), as well of Everest to explore the range of If it resulted from muscle fatigue as the role of mechanoreceptive adaptive physiological responses or failure to execute a motor afferent feedback in baroreflex that ameliorate a fall in tissue programme correctly, the probable function and cardiac vagal tone oxygen delivery at altitude. How answer to this question is yes, and (John Coote), reveal the extent to these processes are modified during these are preventable circumstances. which truly integrative physiology acclimatisation, and their effect on Richard Fergusson points out that a is required to allow fine control to work capacity is examined, changes well-rehearsed motor programme compensate for conflicting stimuli. that cannot be explained solely assumes a certain force output at a The biathlon is an obvious example on the basis of blood PO2 alone. specific time from activated motor of where high aerobic capacity is a Thus, new avenues of discovery units. If this is not the case then, in prerequisite for success, and the role from recreational exertion may the split second available to correct and limitations to performance set provide insight into the genetic and an error or react to an unexpected by the respiratory system at altitude physiological makeup of elite winter change in terrain, all is lost. He and in the cold (Bill Sheel), and how athletes that ultimately determine explains how force output could be the cardiorespiratory system adapts individual performance. depressed, or recruitment strategy to training (John Coote) and altitude could be altered, during exercise (Ben Levine), are explored. However, The full issue is now online at: under ischaemic conditions. Since the biathlon also involves accurate http://ep.physoc.org/content/95/3.toc contractile forces as low as 20% of shooting. Missing a target incurs maximal will occlude blood supply to a time and effort penalty added human calf muscles and quadriceps, by skiing a lap of a circuit, and this it is easy to imagine exercise invariably influences the outcome of conditions where this occurs (e.g. a race. At this point Martin Lakie’s the low tuck position of a downhill expertise on tremor and John skier). In other circumstances, force Coote’s understanding of heart rate may be dramatically reduced at low recovery post-exercise come to the frequencies of stimulation, which can fore. It is clear from these articles Experimental Physiology would like last for up to 48 hours post-exercise. that we still don’t know whether to congratulate Peter Hunter FRS The influence of such low-frequency a high or low pulse rate during (Consulting Editor) on wining The fatigue from an unexpectedly shooting, especially in the standing Rutherfold Medal which is New difficult qualifying event (such as position, is advantageous in terms Zealand’s highest science honour, ice hockey) on the medal deciding of performance. The mechanical along with being made MBNZ in the rounds is evident. Ben Levine correlates of the heart beat and Queen’s New Year Honours in New explains how motor programmes in pulse wave propagation through Zealand for Services to Science. many events need to be retrained to the arm have obvious consequences take account of the lower resistance for accurate sighting on the target. encountered when moving through Whether this error can be avoided, air at altitude. His example of the by having rapid heart rate recovery shorter time taken to rotate the and so potentially a longer interpulse body during a spin in ice dance is interval during which to shoot, or New features in 2010 compelling. Proper allowance for a simply minimised, by having a higher The Journal of Physiology has period of acclimatisation to these heart rate (lower stoke volume and introduced three new features this environmental conditions must hence smaller cardio-ballistic effects) year which aim to provide useful be included in the preparation is debated. additional information for both schedules for competition and also, specialist and non-specialist readers. importantly, on return to normal Intense exercise at altitude may training back at lower altitudes. place an extra strain on energy The online Table of Contents Failure to allow this time is likely supply at a time of reduced (eTOC) of each issue now carries to increase the risk of potentially mechanical efficiency due to low a non-technical summary of all serious injury in a fall or incorrect temperature. Martin Flueck provides research papers in the issue. The idea landing. a timely appeal to consider the behind this feature is that individuals feed-forward as well as feed-back such as students, patients, carers While recruitment of motor units origin of metabolic malleability in or journalists who are searching is modulated by muscle ischaemia, response to endurance training at the internet for information about this may be mediated by afferent altitude, highlighting the genomic physiological terms may come across feedback to the motor pool or and environmental interactions the abstracts of Journal papers but brain. The role of muscle afferent that underlie inter-individual be unable to understand what the feedback in driving sympathetic differences in performance. Daniel paper is about. The non-technical vasoconstrictor tone to active and Martin and colleagues utilise ascent summary will give them this
Physiology News | No. 78 | Spring 2010 | www.physoc.org THE SOCIETY’S JOURNALS PN 55 information in easily comprehensible Summarise your career to date Try to seize opportunities – life is language and should help to spread I took a BA in Natural Sciences, so short that there’s rarely a second a better understanding of physiology University of Cambridge (1977), chance. amongst the general public. and stayed on for a PhD in Zoology Which other scientist (living or dead) (1981), working on ion transport in Review articles in The Journal would you like to have been, and insects with Simon Maddrell. I was now include author profiles. A why? then awarded a Harkness Fellowship, photograph and a short biography which I took at Temple University, August Krogh: he effectively founded of the main author of the review at Philadelphia, working on what would modern comparative physiology, the start of the review helps readers later be known as the V-ATPase. and got a Nobel laureate to boot. to put the article into the context of On my return, I took up a Research If I hadn’t chosen him, it might the author’s expertise and interests. Fellowship of St Catharine’s College have been his son-in-law (Knut It may also boost interest in the Cambridge, for a year, before being Schmidt-Nielsen). articles from readers who follow the appointed a Lecturer in Cell Biology, publications of leaders in their field. at the University of Glasgow in New staff member Finally we have introduced an 1984. After moving around a little, Maev Fitzpatrick experimental series of interviews I became a professor in 1999, and with eminent physiologists. Editor served a term as Head of the Division Brian Robertson interviewed and of Molecular Genetics. I was awarded photographed Eric Kandel for our ScD by the University of Cambridge first article. The highly formalised in 2007. I presently head the style of scientific reporting research theme of Integrative and precludes any familiarity with the Systems Biology. people behind the experiments. What is the best thing about your Our interview answers many of the current position? questions that readers of Kandel’s numerous scientific papers may have Variety. considered as they wonder what it What is the worst thing about your takes to become a leading scientific current position? researcher.The charming portraits Nothing. taken by Brian offer additional insights into the person behind the What is the biggest issue facing I have moved a long way from my science. young physiologists today? home in Cronulla, Sydney, to join The The extraordinary toughness of the Journal of Physiology’s publications New Council Member career path, in the context of the office in Cambridge. In the previous issue of Physiology present financial climate. While surfing my way around News (PN77, pp. 51–53), many of the Why did you stand for Council? Australia and hiking through New new Council Members for 2009 were I care very much about the future of Zealand, I studied for my BA degree included. Here we have answers to physiology. in English and my BSc degree in the same questions from Julian Dow. Anatomy at the University of New Which areas of Council or Society South Wales. During this time I activity would you most like to get gained an interest in science and involved in? publishing. I am particularly excited about the After a period working in the health intersection between physiology department and hospitals in Sydney, Julian and genetics. For most of us, the I decided to pack my bag and take functional and molecular paths are Dow a chance in the UK. I arrived in mutually exclusive from early in our August to catch the end of an English undergraduate careers, and I think this limits our opportunities. ‘summer’ and soon found myself What is your current job(s) title? surfing around Bordeaux and Biarritz, Professor of Molecular and What is your favourite(s) saying or walking in Provence and visiting the Integrative Physiology, and Chair quotation (and who said it)? pubs of Ireland…before starting this of Integrative and Systems Biology ‘Always look on the bright side of great opportunity with The Journal. I research theme, University of life.’ (Eric Idle in ‘Monty Python’s Life am really enjoying working and living Glasgow; and visiting Research of Brian’) in Cambridge despite the serious Professor in Medical and Molecular lack of surf. It was very exciting Genetic Research, King Saud What is the most important thing building my first snowman before University, Riyadh life has taught you? Christmas!
Physiology News | No. 78 | Spring 2010 | www.physoc.org 56 PN OBITUARIES
John Spence Gillespie demonstrate that both the extract and NANC transmission were susceptible 1926–2009 to haemoglobin. Of course, with the John Spence Gillespie, who died on advent of EDRF and nitric oxide, the November 8th 2009, at the age of phenomenon was shown to be nitrergic 83, was Professor of Pharmacology transmission and the explanation for at Glasgow University from 1968 to the long and painful failure to bioassay a 1992. He was the founding Head of the transmitter that was a gas, became clear. Department of Pharmacology from its inception in 1968 until 1988, and served Alongside this scientific career, John ran as Vice-Principal of the University from the gamut of the pressures that attend 1983 to 1991 and Dean of Faculties academic life, particularly if intelligent from 1995 until 1998. He served as and thoughtful, as he was. He took on Chairman of MRC Grants Committees, the job of creating a new Pharmacology on the Committees of both the British Department in Glasgow just after Pharmacological Society (BPS) and taking up the post of Secretary of The The Physiological Society and, as BPS release, stimulated by his work with Physiological Society. Both jobs went representative, on the Editorial Board Brown. That led to an interest in the well. The Physoc is still a going concern of Pharmacological Reviews and on the extraneuronal uptake of transmitters, despite the efforts of some of his Editorial Board for Monographs of The which he pursued with the then new successors and he created a remarkably Physiological Society. He was Honorary fluorescence microscopy technique of cohesive and successful Pharmacology Secretary of The Physiological Society Falck & Hillarp that made noradrenaline Department with a loyal and devoted from 1966 to 1972 and was a Fellow of fluorescent so that it could be seen staff. His twenty year tenure is regarded the Royal Society of Edinburgh. and measured in all cell types. He as a golden period by his staff and by pursued this method with some zest, those who took their BSc or PhD degrees John spent his childhood in the industrial obtaining a large grant to purchase a during that time. Many have followed towns on the Clyde downstream from microspectrograph, a huge machine distinguished careers in universities and Glasgow, where his education was that could carry-out quantitative pharmaceutical companies throughout disrupted by illness and the effects of spectrographic analysis that could the world. the blitz. Nevertheless, he qualified in distinguish various fluorophores derived Medicine at Glasgow University in 1949 from chemically related substances, i.e. Towards the end of his career, John and, after National Service, entered noradrenaline, adrenaline, dopamine, was sucked into senior university a research career. This was initially administration as Vice Principal (Pro-Vice intended as a temporary measure to aid 5-hydroxytryptamine and so on. This was long before the development of modern Chancellor, for Sassenachs) for two his ability to practice medicine, but he terms, surely unnatural punishment. never escaped its allure. He gained his techniques to visualize these differences down the microscope. However, his He said in his recent interview that he PhD working on the innervation of the never enjoyed this but he was extremely colon under RC Garry at the Institute team suffered the usual early-adopter problem that the machine was forever well respected and considered fair and of Physiology in Glasgow then spent even-handed, accounting for his second a productive period with GL Brown breaking down and, as far as I am aware, no published result ever emerged. term in the position. Actually, this at University College London (UCL). characteristic could be infuriating if you Together these mentors kindled his Nevertheless, while doing simple ever got into an argument with him. interest in the known and, at that time, histochemistry with the same technique, Even more than other academics, he unknown, neurotransmitters in the circa 1970, he came across the rat could see six sides of an argument and peripheral autonomic nervous system. anococcygeus muscle, largely because once you wore them down, a seventh. Like many of us, he constantly returned it was full of fluorescent noradrenergic nerves. This fascinated him, of course, to the writings of Langley and his Unlike many, John Gillespie did not haunt because the previous person to mention contemporaries when discussing these his department after retiring. He took up the muscle was Langley. matters, as revealed in a recent interview his interests in painting and gardening, in the Archives of The Physiological and delighting in his grandchildren. He Society. This little preparation offered-up a powerful non-adrenergic, non-cholinergic advised subsequent Principals while His partial shift of focus from physiology (NANC) nerve response, which took him holding the ceremonial post of Dean of to pharmacology is shown by his output back to some of the puzzles in his PhD Faculties. And he left the rest of us to of research papers: roughly one per year project on the colon and, of course, get on with it. This is another lesson that in The Journal of Physiology between 1954 Langley. The rest of his research career many could learn from him. and 1983 and a similar production in consisted of pursuing the nature and He is survived by his wife, Mina, whom British Journal of Pharmacology 1962–94. properties of the underlying transmitter. he married in 1956, sons David, Graeme, Indeed, his research switched direction After a largely futile decade of hitting Adrian and Ian, daughter Ruth and seven several times. After UCL, in 1959 he various assistants’ heads (including grandchildren. went to the Rockefeller Institute in mine) off the brick wall of ‘what was this New York to add electrophysiology to transmitter?’, progress was made with his armamentarium. He was to return the successful production of a smooth Ian McGrath to this in the 70s when Kate Creed muscle relaxant extract of anococcygeus spent a producutive spell in Glasgow. or the conveniently associated but An obituary by Tom Muir and Billy Martin However, on his return to Glasgow, he much larger bovine retractor penis, in was published in the Glasgow Herald on soon returned to his fascination with collaboration mainly with Billy Martin 12th November 2009: the fate of neurotransmitters after and Ann Bowman. They went on to http://tinyurl.com/ybsqcsn
Physiology News | No. 78 | Spring 2010 | www.physoc.org Main Meeting of The Physiological Society Physiology 2010 30 June - 2 July 2010 University of Manchester, UK
Scientific symposia Abstract submission opens Poster and oral communications Trade exhibition 1 March 2010 Plenary lectures, including: Abstract submission closes Murray Esler Baker Heart Research Institute, Melbourne, Australia 31 March 2010 Nancy Rothwell University of Manchester, UK Roger Nicoll University of California, San Francisco, USA Roger Y Tsien Registration now open University of California, San Diego, USA Kay Davies University of Oxford, UK www.physiology2010.org
New techniques workshops The Society is launching four new workshops in 2010 1. Measurement of Gene Expression using Real-time Quantitative PCR King’s College London, UK; March 2. Introduction to Molecular Techniques University College Cork, Republic of Ireland; April 3. Transfections and Functional Studies University College Cork, Republic of Ireland; April 4. Live Cell Imaging Workshop University of East Anglia, UK; June For more information see our website. www.physoc.org/education
PN78.indd 1 05/02/2010 12:55:57 Figure from Flück (p. 28).
A publication of The Physiological Society www.physoc.org