Featrrt

Manchestermeeting

Ca2*phase esemerge Aminoacidtransporters l#f:#llil'c'r'fex Artof scientificendeavour

)-.----- '^r1-'/4 ij--

* © Jenny Hersson-Ringskog

‘My time is up and very glad I am, because I have been leading myself right up to a domain on which I should not dare to trespass, not even in an Inaugural Lecture. This domain contains the awkward problems of mind and matter about which so much has been talked and so little can be said, and having told you of my pedestrian disposition, I hope you will give me leave to stop at this point and not to hazard any further guesses.’

(closing words of Bernard Katz’s Inaugural Lecture, 1952) PHYSIOLOGYNEWS

Contents The Society Dog

Published quarterly by the Physiological Society

Contributions and Queries Executive Editor Linda Rimmer The Physiological Society Editorial 3 Publications Office Printing House Manchester meeting Shaftesbury Road Physiology and Pharmacology in Manchester Arthur Weston 4 Cambridge CB2 2BS

Tel: 01223 325 524 Features 2+ Fax: 01223 312 849 Ca phase waves emerge Dirk van Helden, Mohammed S. Imtiaz 7 Email: [email protected] Role of cationic amino acid transporters in the regulation of nitric oxide The society web server: http://www.physoc.org synthesis in vascular cells Anwar R. Baydoun, Giovanni E. Mann 12 Not for giant axons only Andrew Packard 16 Magazine Editorial Board Editor Colour and form in the cortex Daniel Kiper 19 Bill Winlow (Prime Medica, Knutsford) Deputy Editor Images of physiology Thelma Lovick 21 Austin Elliott (University of Manchester) Members Affiliate News Munir Hussain (University of Liverpool) The art of scientific endeavour Keri Page 23 John Lee (Rotherham General Hospital) Thelma Lovick (University of Birmingham) Letters to the Editor 25 Keri Page (University of Cambridge) Society News © 2003 The Physiological Society ISSN 1476-7996 Review of Society grants Maggie Leggett 26 Biosciences Federation Maggie Leggett 27 The Society permits the single copying of Hot Topics Brenda Costall 27 individual articles for private study or research. 30 For copying or reproduction for any other SET for Britain Lauren MacKenzie purpose, written permission must be sought Careers’ conferences Sai Pathmanathan 30 from the Society. Sixth Form Workshops: Bristol and Chester Sai Pathmanathan 32 Free CDs Maggie Leggett 32 Opinions expressed in articles and letters submitted by or commissioned from Members, Unbelievable! Mark Cain 33 Affiliates or outside bodies are not necessarily those of the Society. Obituaries Bernard Katz David Colquhoun 34 The Physiological Society is registered in E Geoffrey Walsh John Russell, Martin Lakie, Andrew Packard 39 England as a company limited by guarantee, No 323575. Registered office: PO Box 11319, Emiline Lesly Jervis R.J Levin 43 London WC1V 6YB. Registered Charity No A K McIntyre Uwe Proske 44 211585. David Horrobin Maynard Case 48 Prepared in the Publications Office by Charlene 49 Gibbons, Lydia Grove and Linda Rimmer Book Reviews Noticeboard 52 Printed by The Green Tree Press Limited

Cover photo

From an image supplied by Andrew Packard PHYSIOLOGYNEWS Action Points Guidlines for contributors In this issue BSc Intercalated Bursaries These guidelines are intended to assist The main deadline for receipt of applications is authors in writing their contributions and This issue of Physiology News is 30 June (~10 awards), with a second deadline to reduce the subsequent editing process. special in several ways. of 30 November (~3 awards) for institutions The Editorial Group of Physiology News where projects are not decided until the course tries to ensure that all articles are written has begun. in a journalistic style so that they will One is that it contains an article Membership applications have an immediate interest value for a looking forward to the upcoming joint The deadlines for receipt of Full Membership wide readership and will be readable and meeting with the British application forms during 2003 are the last day comprehensible to non-experts. In Pharmacological Society (BPS). In the of September and December particular, scientific articles should give a good overview of a field rather than focus present scientific climate, closer links Change of address on the authors’ own research. with our sister societies are critical to Members should inform the Administration Office of any changes of address, telephone, Format of articles our success. The Physiological Society fax or email addresses. The main message or question posed and the BPS share members, and should be introduced in the first Changes can be emailed to: [email protected] many common interests, perhaps most paragraph. The background for the topic or updated online at www.physoc.org should then be established, leading up to critically in the future of in vivo the final dénouement or conclusion. research. Forthcoming scientific meetings Length of articles This will be determined by the subject This issue also contains a hidden Manchester (9–12 September 2003) matter and agreed between the theme - the importance and richness of Joint meeting with the British Pharmacological contributor and the commissioning Society editor. Articles will vary in length from visual information and how it can be Abstract submission period closed 500 to 2,000 words. used in scientific investigation and Submission of articles communication. Thelma Lovick Cambridge (17–19 December 2003) Authors should submit text in the form launches a new series on Images of of a disk or emailed Word document physiology, with a range of examples Abstract submission period 15–24 September accompanied by a printout wherever 2003 possible. Use of disks reduces the risk of you might not be expecting. Andrew introduction of errors during re-typing. It Packard illustrates beautifully how Glasgow (29–31 March 2004) is helpful to give brief details of the looking carefully at cephalopods computer, operating system and software reveals incredible detail about their package(s) used. Abstract submissions physiology, while Daniel Kiper reports Submission deadlines Authors should submit their abstracts online. Please contact the Executive Editor in the on how the cortex processes colour Full instructions will be available on the Society’s Publications Office (see Contents page for and form. And you can also find out website (http://www.physoc.org/Meetings/future/html) details) for submission deadlines. Late from the opening day of the abstract submission how to demonstrate important submissions may be deferred to a period. properties of the human visual system subsequent issue. with an old shoebox (see p. 42). Illustrations and authors’ photographs Physiology News Authors are encouraged to submit Letters and articles and all other contributions diagrams, drawings, photographs or other Finally, the issue is truly special for inclusion in the Winter issue, No. 53, artwork to illustrate their articles or, if because it contains an appreciation of should reach the Publications Office by they cannot provide these themselves, to the life and work of Sir Bernard Katz, 2 September 2003. Late copy can be included suggest appropriate illustrations. A if space permits. photograph of the author(s) should also one of the giants of 20th century accompany submissions.Photographs physiology, who passed away earlier may be colour or black and white, prints this year. Quite apart from his Suggestions for articles or transparencies or TIFF files with a towering scientific achievements, Suggestions for future articles are welcome. minimum resolution of 300 dpi. Please contact either the Executive Editor or a Electronic colour figures should be saved Bernard Katz lived a remarkable life, member of the Editorial Group of Physiology in CMYK mode. and David Colquhoun’s obituary does News References it, and the man, full justice. (see contents page for details). Authors are requested to keep the number of references to a minimum – preferably Physiology News Online no more than two or three. Please cite all references in the style of The Journal of Physiology News is now available on our Physiology (see Instructions to Authors website: http://www.physoc.org. 2003, http://www.physoc.org). PHYSIOLOGYNEWS PN 3

Others are writing more speculative Having said this, there are clearly Magazine policy pieces containing scientific limits. If someone has a personal axe hypotheses or arguments. to grind, they should not expect us to It is one of the inevitable things provide a forum for them. We will about producing a magazine like And still other contributors are not publish anything deliberately Physiology News that it will, sooner writing, effectively, scientific inflammatory or derogatory. But or later, print something that is journalism. beyond this, as far as possible, we are factually incorrect. committed to not censoring anyone’s In these latter two cases - and views. Sooner, if the editors are unlucky and especially the last one - does that the contributors are careless. Later, if mean the contributors don’t check The other thing to say about the editors are lucky and the their facts? No. Physiology News is that we are contributors are careful. But, always looking for contributions. eventually, something will get Does it mean they can write any old through. See, for instance, the letters rubbish? No. Ideas for new features. Ideas for one­ column in the last issue. off articles. Ideas for themed issues. Does it mean what they say is vetted Cartoons. Jokes. Book reviews. This comes with the territory. A to conform to an accepted view? No. Addresses of interesting websites. magazine, even one published by a Anything. learned scientific society, is not, can Does it mean they can write not and should not be a peer-review something completely one-sided? No Don’t all write at once. journal. The job of a magazine like – unless what they are writing is a Physiology News is to publish useful, letter, or is clearly a piece of Or – do all write at once. informative, and hopefully also advocacy or opinion. entertaining pieces that have But either way, it’s your magazine, so something to do with physiology and In which case it will be identified as write! physiologists and their concerns. just that – as an opinion or personal view. Austin Elliott We could just fill the pages entirely with Society announcements, and Getting back to the first point, what reprint a few university press releases should happen when a magazine like Colin Blakemore and articles borrowed from other Physiology News publishes something publications. But why bother? that is factually incorrect?

Instead, we are committed to It should acknowledge the error, and bringing you something worth publish, if appropriate, letters from reading. the membership and anyone else pointing out the mistake. The people writing for Physiology News are asked to write what they And then it should move on. think. What they think – not necessarily what the Society’s Council Next, what about opinions expressed thinks, or what the editors of the in the magazine? magazine think. Repeat: the contributors are not writing journal Again, the answer is clear. If a writer As this issue reaches the membership papers. But they are writing expresses a view that other Society our President, Colin Blakemore, will scientific content for a scientific members disagree with, they have a be preparing to take up his new post readership. way to respond – they should write in as Chief Executive of the MRC on 1 and disagree. The open debate that October. All the members of the Some are writing informative follows is a sign of a healthy Society will want to extend summaries of their own, or other magazine and of a healthy Society. congratulations to Colin on his people’s, work, or discussing recent An example of this can be seen in the appointment, and wish him the very scientific advances, along the lines of article by Reade in Physiology News best in this new role. Colin has News and Views articles in journals. 49, and the response by Terry always been a powerful advocate for Pure science, and a chance to put Bennett and Sheila Gardiner in the biomedical research and for UK their work in a shop window in front following issue. bioscientists. We cannot think of an of a highly informed scientific individual better suited to head up audience – you lot. That is how it is supposed to work. this key agency. 4 PN MANCHESTER MEETING

Physiology and Pharmacology in Manchester

Following another reorganisation this and to design a new logo for the after the successful RAE 2001 result, emerging institution. All that is there are now eight Divisions within certain is that September 2003 will the School of Biological Sciences. see the very last meeting of our two Many of the Societies’ members Societies in the present Victoria belong to the School and are located University of Manchester. in the Divisions of Physiology, Pharmacology and Toxicology New buildings (PPT), Neuroscience and Integrative When the Physiological Society last Biology. Others work in the met here in March 1999, the so-called Stopford Building, but are members Incubator Building (for start-up of the Faculty of Medicine and some companies) had just been completed of those currently at the University of and the Wellcome Clinical Research Manchester Institute of Science and Centre was being planned. These are Technology (UMIST) will physically now established features of the move to the Stopford site during landscape and were the forerunners 2004. It is difficult for insiders, let of a massive bioscience building alone visitors, to keep track of all programme now underway around these changes but in the following the Stopford Building. Thus, work paragraphs, I highlight some of the will soon start on ‘Incubator 2’, the exciting on-going developments. new Bioscience (ICMCB) Building (£50M) will be occupied during 2004, The merger with UMIST – work on the MIB Building (£20M) Project Unity on the UMIST site will soon start Top: Arthur Weston (Leech Professor of Pharmacology The University of Manchester is and the planning of the new Centre and co-organiser of the Circulation Symposium), merging with UMIST, a move which for Neuroscience (£20M) is well above: Maynard Case (Dean of Biological Sciences) will significantly consolidate and underway. and below: Mark Dunne, the new head of ‘PPT’ strengthen biological sciences’ education and research in Teaching Manchester. Formally the merger will Undergraduate teaching of be completed by September 2004 Physiology and Pharmacology takes and, in these days of branding and place under the auspices of the imaging, the united institution may Medical Biosciences Board. If one have a completely new name. includes the degree of BSc in Rumour has it that consultants are Neuroscience in the calculation, being paid large sums to formulate approaching 200 undergraduates are currently being trained in Physiology and Pharmacology and many of them will graduate with one or both these names in their degree title. The figure is even larger if the BSc in Biomedical Sciences is taken into account.

The training of undergraduates in laboratory techniques has always been a Manchester strength and we have just spent nearly £500K on capital equipment for the multi-user teaching labs. Working closely with the Home Office and with the help of special funding from the Pharmacological Society and from Industry, our students continue to The £50M ICMCB building in June, 2003. Occupation is scheduled for April, 2004 receive an unparalleled grounding in FEATURES PN 5 in vivo techniques. With the Pharmaceutical Industry’s increasing requirement for graduates with these skills recently highlighted (see Frantz (2003). Nature Reviews, Drug Discovery 2, 801), our considerable investment in this aspect of their education is a major success.

There is continuing expansion of our four year courses in Physiology and in Pharmacology with Industrial Experience. Formerly known as Sandwich degrees, these provide an unrivalled 12 months’ training in research and experimental design. Caroline Dive (above, front row, far right) and her group (above) focus on the molecular mechanisms that couple From July 2003, 25 of the very best the damage inflicted by anticancer drugs in tumour cells to the process of apoptosis. Craig Smith, Royal Society students in Physiology and Fellow, and his group (below) are clarifying the role of urea transporter proteins belonging to the UT-A sub-family Pharmacology (who have just completed their second year studies) will be studying outside Manchester in the UK, Germany, Switzerland and the USA. In our experience, it is from this group that the future leaders in Physiology and Pharmacology emerge.

A selection of personalities Maynard Case is currently the Dean of Biological Sciences, a huge task made even more demanding by Project Unity. In spite of this, he and Martin Steward continue to explore the mechanisms of bicarbonate and water transport in the pancreatic duct receptor in cellular calcium Phys Soc’s 2002/2003 GL Brown and to use cultured epithelial cell homeostasis. Lecturer and having only recently lines as models for investigating the stepped down as the Society’s roles of acid-base transporters, Richard Prince who was recruited Meetings Secretary. Mark has aquaporin water channels and tight from the Mayo Clinic to work on the retained academic links with Sheffield junction proteins. pharmacology of nicotinic and his research now embraces the cholinoceptors will shortly be joined area of developmental competence in An on-going strategy is to by Liz Fitzgerald (from London) and the human fetal pancreas and the consolidate research efforts in the Kath Hinchliffe (from Cambridge). generation of insulin-secreting diverse field of receptors, ion These two new appointees will cultures from human embryonic stem channels and transporters. Work in establish their own groups in the cells. From 1 July, Mark will be the Peter Brown’s lab is focused on areas of calcium channels and lipid new Chairman of the Division of cation-chloride cotransporters while signalling, respectively. Physiology, Pharmacology and Craig Smith’s group is clarifying the Toxicology. role of urea transporter proteins Another recent appointment is that belonging to the UT-A sub-family. of Gillian Edwards. A research Caroline Dive’s group focuses on the Five mouse UT-A isoforms have now colleague of mine for many years, we molecular mechanisms that couple been identified and structure-function continue to work on endothelium­ the damage inflicted by anticancer studies are now under way. derived hyperpolarizing factor and drugs in tumour cells to the process on the pharmacology of vascular of apoptosis. One of her specific Now well-established, Daniela potassium channels especially those interests is whether c-Src, an Riccardi and Donald Ward employ a with two-pore domain subunits. oncogenic kinase that is routinely range of molecular and physiological elevated in colon cancer can be techniques to investigate the role of Mark Dunne joined us on 1 March. modulated to promote drug-induced the extracellular calcium-sensing He needs no introduction, being the apoptosis. From September she will 6 PN MANCHESTER MEETING be based at the Paterson Institute link between calcium and where she will direct the cancer vasomotion. Also involved in these pharmacology labs. vascular studies is Mike Taggart who is a member of the Maternal-Fetal Within the Division of Neuroscience, Health Research Centre, along with new appointee Stuart Allan is part of Colin Sibley (convenor of the Phys Nancy Rothwell’s group investigating Soc’s Placental and Perinatal Special the mechanisms of neuronal death Interest Group), Sue Greenwood, and the role of cytokines, particularly Paul Speake and Mark Wareing. interleukin-1 and other inflammatory Their work focuses on various molecules. aspects of pregnancy including placental function, myometrial Following his move to Manchester contractility and control of vascular from Kiev, Alex Verkhratsky’s lab is reactivity in mother and placenta. fully operational and dedicated to investigating the role of the Closing thoughts endoplasmic reticulum in neuronal In the above paragraphs, I have given calcium signalling. These studies will a personal view of how Physiology lead to a better understanding of and Pharmacology stand in neurodegenerative disorders such as Manchester. The old departments of diabetic peripheral neuropathies and Physiology and of Pharmacology they complement those of David may be long gone but the two Tomlinson and Paul Fernyhough, subjects have never been in better both recent appointments from shape. Applications for London. Their work on diabetic Peter Brown (top) is Senior Lecturer in Physiology and undergraduate places are buoyant, organiser of the Transporter Symposium. Bagi neuropathy should form the basis for Nadarajah (above) has recently begun work on there are new faculty appointments, the identification of novel drug mechanisms underlying the development of the the research is ‘5-star’ and we are targets and treatments for use in this cerebral cortex, with respect to neuronal migration and building and innovating. There is a widespread disease state. the early development of cortical neurones buzz and dynamism about the place which impresses all our visitors. Two further important developments cognitive factors in eye movement are the recent appointments of Risto control. A warm welcome awaits you. Come Kauppinen (from the University of and see. Kuopio) and Bagi Nadarajah (from Cardiovascular studies are well London). Risto is creating a new represented in Manchester and the Arthur Weston* group of in vivo NMR brain imaging, work of Richard Balment and Nick Ashton (both in the Division of *Arthur Weston is Leech Professor of Pharmacology. He is a the primary focus of which is the Trustee of the British Pharmacological Society and its Honorary investigation of neurodegenerative Integrative Biology) ranges from fish Treasurer. disorders. Bagi is working on to mammals. Some of their current 2+ mechanisms underlying the interests include altered Ca development of the cerebral cortex transport in diabetes and the with respect to neuronal migration offspring of diabetic pregnancy, non­ University of Newcastle- and the early development of cortical genomic actions of aldosterone and upon-Tyne, April 2003 neurones. the cardiovascular and renal actions A meeting of the Physiological of urotensin II. Recent imports from Society, kindly sponsored in part by Shortly moving to the Stopford site Liverpool in the varying forms of GlaxoSmithKline, took place in will be Graham Barnes and his David Eisner, Stephen O’Neill Newcastle-upon-Tyne during April. sensorimotor group from UMIST. (convenor of the Phys Soc’s Heart Those attending the dinner at the Perhaps their most important and Cardiac Muscle Special Interest Baltic were lucky enough to have a achievement in recent years has been Group), Andy Trafford and Mary preview of Antony Gormley’s new to demonstrate that the rapid Díaz are located in the School of work, Domain Field, as well as predictive response observed in Medicine. Their research interests Allotment, Fruit, Body and Earth, oculomotor control is accomplished range from the cellular mechanisms which brings together for the first through the combined action of involved in the cardioprotective time three groups of his work made short-term storage and timing effects of polyunsaturated fatty acids over the last 10 years. Those who estimation. They are currently to the phenomenon of alternans. missed it can visit: investigating the limitations of Complimenting their cardiac studies sequence learning in hand and eye are the vascular investigations of http://www.balticmill.com/html/viean2.html coordination and the role of Clare Austin who is researching the FEATURES PN 7

Ca2+ phase waves emerge Biology continues to astonish even in well-studied areas.The discovery of long-range Ca2+ phase waves presents one such example.Dirk van Helden and Mohammad Imtiaz explain

was generally assumed that 1993). Thus Ca2+ stores appear to pacemaking arose through a cardiac­ control electrical pacemaking in these like pacemaker model involving preparations. cyclical activation of voltage­ dependent channels in the cell The problem of store plasmalemma. The temptation synchronicity caused by observing the ‘hearts’ These findings, while most pumping away was too much and interesting, left one rather major soon my microelectrodes strayed perplexing problem. This was the Mohammad Imtiaz from the venous preparations to problem of how stores could achieve recording from the lymphatic smooth sufficient synchronicity to drive large muscle. lymphatic ‘hearts’. The much larger smooth muscle syncytium in such Significantly these vessels, like the chambers exhibits very low input arteriolar preparations first prepared resistance and would require large by David Hirst and Tim Neild and currents to drive it, necessitating subsequently the small veins I had highly co-ordinated store release. been working on, could be cut into How might stores achieve such electrically short segments. This synchronicity? The vein studies had meant that voltages generated by shown that STICs show a broad spontaneous or injected currents range of amplitudes and could be Dirk van Helden could be recorded with little very large, suggesting that there was decrement across the syncytium of substantial synchronisation of store Lymphatic pacemaking smooth muscle cells. Indeed, in the release within and possibly across 2+ Evidence that Ca phase waves can mesenteric lymphatic preparation, cells. Evidence for synchronisation of underlie both pacemaking and signal 2+ some of the very short ‘hearts’ IP3R-mediated Ca release was also propagation has derived from studies operated as independent electrically provided by the observation that a on smooth muscle. My (i.e. DvH’s) short preparations due to the smooth summation of these events could act interest in pacemaking first arose muscle being discontinuous in the as the lymphatic pacemaker during studies investigating the region of the valves. Intracellular potential, triggering the generation of properties of spontaneous transient recordings made from electrically lymphatic action potentials. depolarizations in mesenteric veins. short lymphatic preparations led to These events proved of particular the first major surprise, as action Synchronicity through interest as they were determined to be potentials were found to be generated diffusion-based Ca2+ waves ­ 2+ generated by spontaneous Ca by spontaneous transient still insufficient release events, each such event depolarizations with properties A possible solution to this mystery, generating a spontaneous transient analogous to those observed in the was provided by the reports of Ca2+ inward current (STIC) (van Helden, venous preparations (van Helden, waves where release from one store 1991) (Fig. 1). As such they presented a corollary to reports of spontaneous transient outward currents (STOCs) but now being excitatory. Adjacent to these vessels were lymphatic vessels that often exhibited spontaneous contractions. These vessels are divided into multiple chambers by unidirectional valves with each chamber acting as a ‘primitive heart’ to pump lymph. At this time (1986-89), there was little knowledge about the pacemaker mechanism in these ‘hearts’ and it Figure 1. A Ca2+ release event in a lymphatic smooth muscle cell generates a spontaneous transient inward current (STIC) and resultant spontaneous transient depolarization (STD) 8 PN FEATURES activates release of the adjacent laboratory on the canine colon (Liu that led to coupled oscillator-based stores. This occurs through calcium­ et al. 1995) arrived at the same models being applied to biological induced calcium release (CICR) from conclusion, namely that Ca2+ stores rhythms, as first applied to model either ryanodine receptors (RyRs) or were pacing slow waves. heartbeats (van der Pol & van der inositol 1,4,5-trisphosphate receptors Mark, 1926) and subsequently to

(IP3Rs) present in the Importantly, these findings were interpret gastrointestinal slow waves sarcoplasmic/endoplasmic reticulum constrained by the same impasse. While these models were of cells. Thus group activation of How could stores achieve sufficient mathematically based with no stores could occur by this mechanism synchronicity to pace the regenerative understanding of the underlying which, in the case of lymphatics, slow waves? Furthermore, in visceral biological oscillators, they provided would occur by sequential activation smooth muscle there are additional great interest and various research of IP3Rs. However, there is a caveat complexities. First, the pacemaker groups have continued to argue even with this mechanism as Ca2+ cells are proposed to be a different strongly for such mechanisms (e.g. waves have been reported to conduct type of cell termed Interstitial Cells of see Daniel et al. 1994). This coupled relatively slowly (typically 0.002 - 0.1 Cajal (ICCs), with one type present oscillator model provided the next mm/s) and would activate relatively in specific networks in the myenteric ‘brick in the road’ to understanding few cells given the smooth muscle cell plexus (ICC-MP) and another store synchronicity. length is the order of 0.1 mm and present intramuscularly (ICC-IM). Ca2+ release events and resultant Second, and most importantly, it was Diffusion-linked Ca2+ stores STICs are brief (e.g. < 0.3 s). As not known how the signal interact as weak coupled such, even this mechanism is likely to propagated across the vast number of oscillators be severely limited in its ability to cells to, in many cases, produce near Ca2+ stores are oscillators and are induce sufficient current to drive synchronous contractions (e.g. clearly coupled by at least one factor guinea-pig lymphatic chambers to circumferential contractions of the (i.e. the diffusion of Ca2+) within and threshold, let alone those in the stomach including those of large presumably across the cellular lymphatics of larger animals. animals are near synchronous syncytium. We predicted coupling Therefore, the question of how stores providing optimum ‘squeezing’ of to occur through active stores synchronise had not been resolved. stomach contents). This does not undergoing oscillatory Ca2+ release occur by voltage-dependent channels advancing or retarding the cycle of Slow waves also require commonly associated with action adjacent stores by CICR until massive store synchronicity potentials, as slow waves occur and entrainment was achieved. It was The pathway through this impasse propagate in the presence of TTX or time to undertake simulations of 2+ came during a brief sabbatical visit to L-type Ca channel blockade. these interactions as made with Mike the laboratory of Hikaru Suzuki at Sculley and subsequently with my Nagoya City University in the Synchronicity through graduate student Mohammad Imtiaz. beginning of 1995. Here, I was coupled oscillators To do this we used existing models introduced to recording slow waves A major advance to explaining the used for modelling sequentially in a visceral smooth muscle requirement for massive store conducting Ca2+ waves involving a synchronicity came when back in my preparation and to the preparation of one-dimensional array of IP3R­ own laboratory. There was an electrically tractable single bundles of operated stores capable of oscillatory ongoing controversy of how slow this preparation, the latter provided Ca2+ release as stimulated by IP waves propagate, with a cardiac type 3 by the much appreciated help of and/or Ca2+. The primary difference Takeo Itoh. While long studied, the model (i.e. action potential-based propagation) contrasted against a was that we applied the stimulus origin of these waves was still globally over the tissue. The result unknown. A surprising similarity in long held alternative model, based on the concept of synchronisation of was weak coupled oscillator-based the appearance of this activity to synchronisation. An important paper lymphatic pacemaker activity led to coupled oscillators. Coupled oscillator-based interactions were appeared during this period, using pharmacological experiments the same type of simulation showing 2+ first described for an array of investigating a role for Ca stores. that Ca2+ waves in astrocytes could Importantly, the results paralleled pendulums that, when linked (e.g. by be explained as arising through Ca2+ those of the lymphatics indicating springs) and randomly activated, stores interacting as coupled that stores were driving pacemaking. entrain their activity over time. The oscillators (Roth et al. 1995). In their This same approach was also applied result is a phase wave in which each case the coupled oscillator-based to slow waves in the guinea-pig oscillator has the same frequency of interactions, while weak, could urethra resulting in the same outcome oscillation but with a spatial explain the measured ‘propagation’ that stores were driving the slow variation in phase that depends on rates of the Ca2+ waves, which in waves (Hashitani et al. 1996). A key the strength of the coupling between their tissues exhibited ‘apparent publication from Jan Huizinga’s the oscillators. It is these principles FEATURES PN 9 conduction velocities’ (‘CVs’) in the range 5-60 um/s dependent on the level of agonist stimulation and hence intracellular [IP3]. Therefore, we were left with the conclusion that Ca2+ stores could interact as coupled oscillators, but such coupling was weak. This mechanism could not explain slow wave initiation due to the weak synchrony. Secondly, it could not explain slow wave propagation, with slow waves propagating with ‘CVs’ orders of magnitude greater.

Membrane voltage – the ‘missing link’ The next step forward came through the outcomes of experiments being undertaken in the laboratory using finely dissected ‘single bundle’ strips of gastric pyloric smooth muscle (van Helden et al. 2000). Here, we presented evidence that slow waves were composed of a pacemaker and 2+ regenerative component, with both Figure 2. A schematic showing feedback linkages between IP3R-mediated Ca release and membrane depolarization. Store Ca2+ release depolarizes the membrane with this depolarization providing positive feedback to components generated by release 2+ cause further IP3R-mediated Ca release from the SR (from van Helden et al. 2000) from IP3R-operated stores. Thus while the regenerative component of 2+ induce IP3R-mediated Ca release. phase waves emerge in a previously the slow wave outwardly resembles Thus while the small effective quiescent tissue is as follows. an action potential, it is not diffusion range for Ca2+ of < 10 µm Increasing stimulation of stores (e.g. generated by voltage-dependent provides weak coupling between agonist-induced increases in [IP3]i) channels in the cell plasmalemma but stores, coupling by membrane across the cellular syncytium first 2+ by regenerative release from Ca voltage is much more effective. This activates the most sensitive sub­ stores. Significantly, there is voltage­ is so because membrane voltage and plasmalemmal IP3R-operated stores, 2+ dependent feedback on IP3R­ associated current flow has orders of the Ca release events causing local mediated Ca2+ release, with magnitude more ‘reach’ than inward current flow across the depolarization enhancing and diffusion with electrical length plasmalemma. Initially these act hyperpolarization decreasing release. constants typically in the range of independently but as the level of This may result through voltage­ 1–4 mm. The result is that active stimulation increases local dependent production of IP3 but the stores can now synchronise on a interactions increase to generate same outcome would arise if the grand scale through long-range larger coordinated events underlying depolarization acted by an parallel interactions. It is this voltage measurable spontaneous transient intermediate step, such as enhancing link which underpins the emergence depolarizations. With further 2+ 2+ [Ca ]i, with this intermediate then of long-range Ca phase waves. stimulation the number of these enhancing production of IP3 (Fig. 2). events increases across the cellular Similar findings were also reported in Store synchronicity through syncytium leading to more global strips of gastric antrum (Suzuki & long-range Ca2+ phase waves synchronisation and resultant 2+ Hirst, 1999). Our recent paper and simulation coordinated pacemaker Ca release (van Helden & Imtiaz, 2003) presents and associated pacemaker The link between membrane potential experimental and model-based depolarization. As spatial and store Ca2+ release provided the evidence for the existence of these synchronisation is imperfect, there is 2+ key to solving the question of how Ca2+ phase waves. The findings were a phase delay between Ca release stores could synchronise on a massive again made using fine ‘single bundle’ across the array of stores and the scale. Now stores are not simply strips of guinea-pig pyloric smooth pacemaker Ca2+ release takes the linked by the diffusion of store muscle but now mostly using form of a Ca2+ phase wave. This is activators alone but also by electrically long tissue strips of length presented in the schematic of Fig. 3, membrane voltage in its capacity to up to 10 mm. Our view of how Ca2+ which for simplicity uses a pendulum 10 PN FEATURES analogy. Further stimulation and not stop transmission. Rather, the The role of specific ‘pacemaker cells’ associated recruitment of stores, by slow waves persisted at the two strip is also readily accounted for, these the pacemaker Ca2+ release together ends but now showed no phase corresponding to cells that more with the associated depolarization, correspondence with each other. This readily undergo oscillatory Ca2+ causes the sub-plasmalemmal [Ca2+] indicates that interactions are release with their oscillatory cycle in and/or [IP3] to reach threshold for occurring by coupled oscillator-based turn entraining cells with less regenerative activation of the large mechanisms. A role of stores and the sensitive Ca2+ stores. Importantly, the population of less sensitive stores. importance of electrical coupling proposed feedback between 2+ This results in regenerative Ca between stores were indicated by depolarization and production of IP3 release and associated slow wave central application of an inhibitor as used in the modelling studies 2+ that blocks store release but does not potential. The Ca phase waves are indicates the co-existence of IP3­ now much larger reflecting a interrupt cellular connectivity. This phase waves. These are predicted to pacemaker and a regenerative produced the same result but operate hand in hand with the Ca2+ component with the average cycle required a much wider central region phase waves. time of the entrained stores of inhibition commensurate with the determining the frequency and the hypothesis that stores were primarily Significantly, very high levels of phase delay the ‘CV’ of the resultant coupled by membrane voltage and agonist stimulation can cause 2+ slow waves. not by diffusion of Ca . In desynchronisation and failure of slow summary, the findings indicate that waves. Our simulations suggest that stores interact as coupled oscillators Part of the evidence for Ca2+ phase this occurs because the frequency of and that membrane potential is a key waves was based on a type of store oscillations, which is known to linking factor between the stores. experiment made by A.L. Hodgkin in increase with agonist concentration , 1939. He found that alteration of the becomes too high so that existing Simulations made by modelling the conduction pathway in a central delays in the feedback between tissue as an array of IP R-operated region of a nerve axon modulated the 3 membrane voltage and store release stores with a Gaussian distribution of action potential CV and in one case become significant with resultant sensitivities mimic all the action potential conduction was weakening in store coupling. experimental findings. These interrupted dependent on the simulations again confirm the Lymphatic vasomotion effectiveness of conduction in the fundamental importance of linking central region. This latter observation The same hypothesis can also be membrane depolarization to IP3R­ applied to lymphatics, as we together is entirely consistent with the action 2+ potential conducting sequentially. In mediated store Ca release. with Jun Zhao have recently contrast, an analogous experiment Significantly, the tissue can operate communicated. The key to store performed on a strip exhibiting slow effectively independent of tissue size synchronicity is again feedback waves made by chemically due to the distributed nature of the between membrane depolarization. interrupting the connectivity between pacemaker, with each cell likely to However, now the link is primarily cells near the middle of the strip did drive its own regenerative response. due to depolarization induced opening of L-type Ca2+ channels and resultant calcium-induced calcium release from the stores. Ca2+ stores within the smooth muscle syncytium are now strongly coupled by membrane voltage and synchronise to produce pacemaker potentials that trigger action potentials and constrict the lymphatic ‘hearts’.

Such constrictions are a type of vasomotion and in this regard it is interesting to note a recent hypothesis for vasomotion (Peng et al. 2001). Here initial uncoordinated Ca2+ release is considered to synchronise when ‘sufficient number of cells become active at the same Figure 3. Coupled oscillators as exemplified by pendulums coupled by springs to their nearest neighbours. The moment’. The resultant inward effect of voltage-dependent IP3 synthesis is illustrated by a system of pendulums coupled through multiple springs current now overcomes the current extending over the array of pendulums. These oscillators when randomly activated can entrain to produce a phase wave sink in the preparation and FEATURES PN 11

depolarizes all cells to open L-Ca2+ Future directions role in heart pacemaking and 2+ 2+ channels, the resultant Ca influx Ca and/or IP3 phase waves may conduction. We make this prediction activating Ca2+ release across the emerge to generate cellular rhythms based on growing evidence for a role cells. Significantly, Ca2+ phase waves when cells: of stores, as an important source of provide a means by which biology pacemaker current and through the ensures that sufficient number of cells 1. exhibit oscillatory IP3R- or RyR­ strong linkage between membrane 2+ do become active at the same mediated store Ca2+ release; potential (i.e. voltage-dependent Ca moment. Consistent with this, there is 2. depolarize in response to store entry) and store Ca2+ release. Perhaps direct proof in the literature that Ca2+ release; this store-based mechanism of lymphatic vessels constrict through a 3. demonstrate increased store Ca2+ pacemaking, as first observed in coupled oscillator-based process. This release upon membrane lymphatic ‘hearts’, may prove to be derives from studies on bovine depolarization and less ‘primitive’ than previously lymphatics (McHale & Meharg, 4. are interlinked through gap thought. 1992). Here central interference with junctions or other pathways. pacemaking by either reduction in Dirk F.van Helden & temperature or application of Physics tells us that arrays of Mohammad S.Imtiaz heptanol (10 mM), an agent likely to The Neuroscience Group, School of Biomedical oscillators that are strongly coupled Sciences, University of Newcastle, NSW, Australia block intercellular connectivity entrain when sufficiently stimulated. caused the near synchronous 2+ Therefore Ca stores in such cell References contractions along the vessel to systems should interact as strongly Daniel EE, Bardakjian BL, Huizinga JD & Diamant NE (1994). Relaxation oscillator and core conductor models are needed for decouple. coupled oscillators, exhibiting understanding of GI electrical activities. Am J Physiol 266, G339­ emergent local near synchronous 349. 2+ Voltage-accelerated Ca 2+ oscillations and long-range Ca Hashitani H, Van Helden DF & Suzuki H (1996). Properties of waves phase waves. spontaneous depolarizations in circular smooth muscle cells of rabbit A point made in our study (van urethra. Brit J Pharmacol 118, 1627-1632. Helden & Imtiaz, 2003) is that local In such systems pacemaker frequency IJLiu LW, Thuneberg L & Huizinga JD (1995). Cyclopiazonic acid, 2+ inhibiting the endoplasmic reticulum calcium pump, reduces the stimulation of Ca release could lead would be determined by the cycle canine colonic pacemaker frequency. J Pharmacol Exp Ther 275, to production of accelerated time of the entrained stores and ‘CV’ 1058-1068. 2+ sequentially conducting Ca waves. by the synchronicity of the phase McHale NG & Meharg MK (1992). Co-ordination of pumping in This is considered to occur in the waves. As for the former, we note isolated bovine lymphatic vessels. J Physiol 450, 503-512. gastrointestinal smooth muscle that Ca2+ phase wave-based Peng H, Matchkov V, Ivarsen A, Aalkjaer C & Nilsson H (2001). through the voltage-feedback pacemaking can theoretically exhibit Hypothesis for the initiation of vasomotion. Circ Res 88, 810-815.. producing enhancement in IP3R­ an enormous range of frequencies Roth BJ, Yagodin SV, Holtzclaw L & Russell JT (1995). A mediated Ca2+ release, this process mathematical model of agonist-induced propagation of calcium (e.g. <0.1 to >10Hz), consistent with waves in astrocytes. Cell Calcium 17, 53-64. then continuing in sequence along the reported store cycle times. We also tissue. In the likely event that the Suzuki H & Hirst GD (1999). Regenerative potentials evoked in note that the ‘CV’ may also show a circular smooth muscle of the antral region of guinea-pig stomach. J feedback between membrane large range depending on factors Physiol 517, 563-573. 2+ potential and IP3R-mediated Ca such as the connectivity of cells and van der Pol B & van der Mark J (1926). The heartbeat considered as release is due to increased [IP3], then the strength of the positive feedback a relaxation oscillation, and an electrical model of the heart. Phil there will be both a sequential between membrane depolarization Magnus Suppl. 6, 763-775. 2+ voltage-accelerated IP3 wave and and store Ca release. van Helden DF (1991). Spontaneous and noradrenaline-induced 2+ transient depolarizations in the smooth muscle of guinea-pig resultant Ca wave. However, while mesenteric vein. J Physiol 437, 511-541. such rapidly conducting sequential Ca2+ phase wave-based pacemaking van Helden DF (1993). Pacemaker potentials in lymphatic smooth waves are likely to be very important, as presented here is sufficiently novel muscle of the guinea-pig mesentery. J Physiol 471, 465-479. the normal modus operandi of the to allow some speculation. First, we van Helden DF & Imtiaz MS (2003). Ca2+ phase waves: a basis for rhythmically active tissues of our predict it to underlie many cellular cellular pacemaking and long-range synchronicity in the guinea-pig studies (i.e. pyloric and lymphatic rhythms including specific brain gastric pylorus. J. Physiol. 548.1, 271-296. smooth muscle tissues) is through rhythms, the brain being replete with van Helden DF, Imtiaz MS, Nurgaliyeva K, von der Weid P & Dosen stores interacting as coupled both IP3Rs and RyRs. Second, it PJ (2000). Role of calcium stores and membrane voltage in the generation of slow wave action potentials in guinea-pig gastric oscillators. seems possible that it will also have a pylorus. J Physiol 524, 245-265. 12 PN FEATURES

Role of cationic amino acid transporters in the regulation of nitric oxide synthesis in vascular cells Anwar Baydoun and Giovanni Mann review the physiological and molecular characteristics of CAT transporters and discuss the role of L-arginine transport in regulating NO synthesis

labile NO is synthesised from the generates quantitatively more NO cationic amino acid L–arginine compared to its constitutive isoforms. following oxidation of the terminal Overproduction of NO by iNOS guanidino-nitrogen by a family of functions as an important mediator enzymes referred to as NO synthases of inflammatory responses and has (NOS). Three distinct isoforms, been implicated in the pathogenesis endothelial (eNOS or NOS I), of various inflammatory and neuronal (nNOS or NOS II) and autoimmune disorders (reviewed by Anwar Baydoun inducible (iNOS or NOS III), have Hobbs et al. 1999). been identified and are known to be derived from separate genes and Source of substrate for NO regulated by diverse signalling synthesis pathways (reviewed by Alderton et The source of L–arginine for NO al. 2001). synthesis appears to depend on the physiological state and biosynthetic Both eNOS and nNOS are pathway being activated. L–arginine constitutively expressed, dependent on it own does not significantly alter 2+ blood pressure in vivo, nor does Giovanni Mann upon Ca and calmodulin for activation, and generate picomolar L–arginine alter coronary perfusion The discovery in 1987 that amounts of NO over short periods of pressure or the tension developed by endothelium-derived relaxing factor time following agonist stimulation. isolated blood vessels in vitro. These is nitric oxide (NO) was followed a Under normal physiological findings suggest that basal NO year later with reports that the conditions, generation of NO via the synthesis is not limited by substrate cationic amino acid L–arginine is the constitutive endothelial L–arginine- availability. L–arginine is present in physiological precursor for NO and NO pathway appears to be a key high concentrations in endothelial in 1998 with the award of the Nobel regulator of vascular tone, cells (~0.8 mM), and the Km of eNOS Prize in Physiology and Medicine for maintaining the vasculature in a for L–arginine is <0.01 mM, with the discovery of NO as a key basal state of vasodilatation. nNOS maximal stimulation occurring in the signalling molecule. Several groups, on the other hand mediates diverse presence of 0.03-0.1 mM L–arginine. including ours, have investigated the neuronal functions accounting, for Thus availability of L–arginine may characteristics and regulation of instance, for the nitridergic not be rate limiting for the relatively cationic amino acid transporters component of peripheral non­ small quantities of NO released under (CAT-1, CAT-2A, CAT-2B, CAT-3) adrenergic, non-cholinergic basal conditions. The same appears in vascular cells. In this article we neurotransmission. to be true for transient stimulation of review the physiological and NO production by various agonists, molecular characteristics of CAT In contrast to its constitutive including bradykinin and transporters mediating L–arginine isoforms, synthesis of NO via the acetylcholine. However, when a influx and discuss the role of L­ inducible pathway involves induction stimulus is applied repeatedly over 2+ arginine transport in regulating NO of a Ca /calmodulin-insensitive prolonged periods, endogenous synthesis. As there are several iNOS, previously identified in substrate becomes rate limiting. excellent reviews on the transduction macrophages and now known to be Under these conditions availability pathways associated with NO induced in a wide variety of cell types and transport of exogenous biosynthesis and signaling, we aim to including endothelial and smooth L–arginine restores responses provide only a brief overview. muscle cells. Expression of this previously rendered tolerant by enzyme is time-dependent, involves repeated or prolonged agonist L–arginine-nitric oxide de novo protein synthesis and can be administration. In this context, pathways inhibited by protein synthesis studies in cultured endothelial cells, Nitric oxide is a free radical with a inhibitors and glucocorticoids. Once perfused tissues, whole animals and multitude of physiological and induced the activity of the enzyme is man have shown that exogenous pathophysiological functions. Highly sustained over prolonged periods and L–arginine can reverse inhibition of FEATURES PN 13

under both physiological and NO exposure on L–arginine pathophysiological conditions. There transport were attributed to the are, however, counter arguments, oxidation of sulfhydryl moieties since vascular cells can metabolise within the transporter protein. At L–citrulline via a truncated urea cycle present there is limited evidence to to generate adequate amounts of suggest that L–arginine transport and L–arginine for sustained NO NO synthesis are directly coupled. synthesis. Consistent with this Instead, these two processes may be hypothesis is that conversion of regulated independently since (i) L–citrulline to L–arginine is increases in L–arginine transport enhanced in endothelial cells occur despite inhibition of iNOS stimulated to release NO, as well as expression by dexamethasone, (ii) in macrophages and smooth muscle inhibition of iNOS with arginine Figure 1. Dependency of LPS/interferon-γ stimulated cells generating NO following analogues such as L-NAME does not nitrite release from rat aortic smooth muscle cells on activation with pro-inflammatory alter cytokine-stimulated L–arginine extracellular L-arginine or L-citrulline. Rat aortic smooth muscle cells were activated for 24h with LPS mediators. However, despite these transport in cultured cells and (iii) (100 µg ml-1) and IFN-γ (50 U ml-1) in L-arginine­ increases in the generation of transfection of iNOS cDNA in cells depleted medium supplemented with increasing L–arginine from L–citrulline, our which do not express iNOS either 4 concentrations of either L-arginine ( ) or L-citrulline ( studies in intact cells have shown that constitutively or in response to pro­ 8 ), with nitrite accumulation used as an index of NO production. in L–arginine deprived cells inflammatory mediators (e.g. L–citrulline cannot sustain maximal HEK293 cells) fails to cause eNOS by inhibitor analogues of rates of NO synthesis (Fig. 1). significant changes in L–arginine L–arginine itself, and enhance or Moreover, as transport of L-citrulline transport despite a significant sustain agonist-induced release of into vascular cells is slow and 3-fold increase in NO production NO from the endothelium. lower than rates measured for (unpublished observations). These Interestingly, the endothelium­ L–arginine, it seems unlikely that findings argue against regulation of dependent component of cyclic L–citrulline transport can sustain L–arginine transporter function by AMP-mediated relaxation in rat maximal rates of NO synthesis in vivo the activity of iNOS. pulmonary arteries is critically (Wileman et al. 2003) dependent on availability of Based on the evidence available, it extracellular L–arginine (see Hucks et Modulation of L–arginine seems that enhanced L–arginine al. 2000). transport by nitric oxide transport in iNOS expressing cells The critical role of exogenous requires de novo protein synthesis. The dependence of NO production L–arginine in regulating NO This may result from the activation on exogenous L–arginine is perhaps production begs the question of by external stimuli of key kinase more apparent with iNOS, the high whether NO can modulate transport signalling cascades of which the p38 output system that generates of L–arginine. Influx of L–arginine is mitogen-activated kinase pathway nanomolar quantities of NO over increased transiently in endothelial may be critical (Baydoun et al. 1999). prolonged periods. Release of NO by cells stimulated with NO releasing In contrast, transient increases in this enzyme is not only dependent on agonists such as bradykinin, ATP or L–arginine transport observed in the presence of extracellular adenosine and elevated in cells agonist-stimulated endothelial cells L–arginine, but also directly related expressing iNOS. Recent studies have may be secondary to a membrane to the rate of L–arginine transport. shown that the NO donors (SNAP, hyperpolarization induced by dipropylenetriamine NONOate) vasoactive agonists (Fig. 2). These findings suggest that acutely stimulate L–ARGININE influx, Nevertheless, we would still like to availability and transport of whereas longer exposure (1-4 h) to postulate that increased cationic L–arginine can limit NO production these NO donors inhibits transport. amino acid transporter activity The inhibitory effects of prolonged provides a mechanism for sustaining 14 PN FEATURES

L–arginine supply during prolonged distinguishable by their structure, revealed a 622 amino acid NO production. distribution and affinity for cationic glycoprotein of about 67 kDa with 12 amino acids. to 14 transmembrane spanning Transport systems mediating domains. influx of L–arginine At least five different CAT proteins L–arginine is predominantly designated CAT-1, CAT-2A, CAT­ A truncated CAT-2 gene was cloned transported across cell membranes 2B, CAT-3 and CAT-4 have been shortly after CAT-1 and initially via specific sodium-independent identified in different mammalian named Tea (T-cell early activation transporter(s) selective for cationic tissues. Some of the key receptor) because of its induction amino acids. This pathway was characteristics of these proteins are early in the response of normal T originally termed system y+. discussed below and summarised in cells to mitogens. The full length Although other systems, including b+, the Table. CAT-4 appears to lack cDNA which encodes a 658 amino bo,+, Bo,+ and y+L, have been cationic amino acid transport acid protein (CAT-2B) was identified as transporters for cationic activity, and CAT-3 is expressed subsequently isolated and shown to amino acids, these carriers also predominantly in brain and thymus have a 61 % homology with CAT-1 accept a wider range of substrates, tissue and also interacts with neutral (see Table) and 98 % homology with including neutral amino acids (Devés amino acids. CAT-2A. It is now known that CAT­ & Boyd, 1998). Thus, the only 2A and CAT-2B are the products of selective cationic transporter differentially spliced mRNAs. The Molecular identification, expressed in vascular cells still deduced sequence of these two structure and function of remains system y+. proteins differ by only 20 amino CATs acids within a stretch of 41 amino Of the five proteins, CAT-1, a high­ System y+ was initially thought of in acids in an alternatively spliced affinity electrogenic transporter, was terms of a ‘one-protein-one transport region in the predicted fourth the first to be characterised at a activity’ paradigm. However, the extracellular loop. molecular level. This protein was evolution of recombinant DNA cloned serendipitously by a group Unlike CAT-1 and CAT-2A, CAT­ technology and the development of searching for the ecotropic murine 2B is an inducible protein (at least in new kinetic experimental approaches leukemia virus receptor (ecoR), and macrophages) with a high affinity for have unveiled a more complex shown to mediate cationic amino L–arginine (K : 0.04 - 0.38 mM) picture. It is now evident that m acid transport when expressed in transport of L–arginine, and indeed comparable to that of CAT-1, despite Xenopus oocytes. The deduced amino other cationic amino acids, involves its high sequence identity with CAT­ acid sequence of the cloned cDNA several distinct proteins which are 2A. This strongly indicates that the divergent domain in the predicted fourth loop of CAT-2 may be critical for substrate recognition and/or translocation. Indeed, substitution of this domain in CAT-2B with that of CAT-2A resulted in a chimeric protein that had a low affinity for L–arginine, while substituting this domain in CAT-2A with that of CAT-1 or CAT-2B resulted in a transporter with high affinity for L–arginine comparable to that of CAT-1 and CAT-2B. These variations in transport properties have recently been attributed to differences in two amino acid residues within the stretch of 42 amino acids in the alternatively spliced region of the human CAT isoforms (Habermeier et al. 2003).

Figure 2. Relationship between L-arginine transport and NO synthesis in vascular cells. Stimulation of endothelial At present we cannot distinguish cells with agonist elevates intracellular Ca2+ and activates both eNOS and Ca2+-activated K+ channels, with the latter resulting in a membrane hyperpolarization and increased transport of L-arginine via CAT(s). Treatment of cells with between CAT-1 and CAT-2B in LPS/cytokines activates specific signalling mechanisms, leading to the induction of iNOS and synthesis of new CAT terms of their relative contribution to proteins involved in the supply of extracellular L-arginine to iNOS for NO production total L–arginine uptake under FEATURES PN 15 normal physiological conditions, nor contribution of each CAT to total result in alterations in the can we specify which CAT directly L–arginine transport in different cell L–arginine-NO signalling pathway supplies L–arginine to NOS in cell systems. Specific knockouts and/or (see review by Mann et al. 2003). system. This latter point is important antisense strategies are clearly Advances in the molecular biology of since there are reports that CAT-1, required to identify the key CAT(s) cationic amino acid transporters and by virtue of its co-localisation with associated with the regulation of NO intracellular signalling pathways eNOS in membrane caveolae supplies biosynthesis. provide a basis for further substrate to this enzyme (Fig. 2), investigating the regulation of whereas CAT-2B, which is induced in Conclusions L–arginine transport in NO parallel with iNOS, critically The identification of distinct generating cells in health and disease. regulates supply of L–arginine to this transport proteins that mediate influx enzyme. Moreover, the finding that of L–arginine provides a basis for Anwar R. Baydoun iNOS mediated NO production is assessing the role of these Biosciences Department University of Hertfordshire significantly reduced in peritoneal transporters in regulating NO Giovanni E. Mann -,- production, though questions remain macrophages from CAT-2B mice Centre for Cardiovascular Biology & Medicine, (Nicholson et al. 2001), strongly concerning the signal transduction King’s College London suggests a functional association pathways involved in the co­ between CAT-2B and iNOS, and a activation of L–arginine transport References and NO synthesis. Future Alderton WK, Cooper CE & Knowles RG (2001). Nitric oxide critical dependency of NO synthases: structure, function and inhibition. Biochem J 357, 593­ production on L–ARGININE delivery understanding of the 615. compartmentalisation of different at least in peritoneal macrophages. Baydoun AR, Wileman SM, Wheeler_Jones CP, Marber MS, Mann CATs may permit the design specific GE, Pearson JD & Closs EI (1999). Transmembrane signalling probes that could be used to mechanisms regulating expression of cationic amino acid The notion that different NOS transporters and inducible nitric oxide synthase in rat vascular isoforms may be directly linked to selectively manipulate expression smooth muscle cells. Biochem J 344, 265-272. and/or function of different CATs. distinct CAT(s) for substrate supply Deves R & Boyd CA (1998). Transporters for cationic amino acids in should however be viewed with This would undoubtedly allow for animal cells: discovery, structure, and function. Physiol Rev 78, 487­ caution, since this may be cell type the physiological role of these 545. dependent. Using isoform-specific proteins and their involvement in Habermeier A, Wolf S, Martine U, Graf P & Closs EI (2003). Two various diseases to be established. amino acid residues determine the low substrate affinity of human probes in RNase protection analyses, cationic amino acid transporter-2A. J Biol Chem 278, 19492-19499. we have identified transcripts for Indeed there are indications that altered L–arginine transport may Hobbs AJ, Higgs A & Moncada S (1999). Inhibition of nitric oxide CAT-1, CAT-2A and CAT-2B in rat synthase as a potential therapeutic target. Annu Rev Pharmacol primary aortic smooth muscle cell contribute to the pathophysiology of Toxicol 39, 191-220. cardiovascular disorders. Acute cultures. Moreover, significant Hucks D & Ward JP (2000). Critical dependence of the NO-mediated elevations in mRNA for all three administration of L–arginine restores component of cyclic AMP-induced vasorelaxation on extracellular L–arginine in pulmonary arteries of the rat. Br J Pharmacol 130, 997­ CAT isoforms were detected endothelium-dependent 1004. following activation of cells with LPS vasodilatation in Mann GE, Yudilevich DL & Sobrevia L. (2003). Regulation of amino and interferon-g (Baydoun et al. hypercholesterolemic patients, and acid and glucose transporters in endothelial and smooth muscle 1999). Enhanced transcript levels for both acute and chronic cells. Physiol Rev 83, 183-252 administration of L–arginine also CAT-1, -2A and -2B have also been Nicholson B, Manner CK, Kleeman J & MacLeod CL (2001). observed in cardiac myocytes normalises impaired endothelium­ Sustained nitric oxide production in macrophages requires the arginine transporter CAT2. J Biol Chem 276, 15881-15885. following treatment with IL-1b and dependent relaxation in vessels IFN-g (Simmons et al. 1996). These isolated from cholesterol-fed rabbits. Simmons WW, Closs EI, Cunningham JM, Smith TW & Kelly RA (1996). Cytokines and insulin induce cationic amino acid transporter findings have now lead to the Recent evidence indicates that (CAT) expression in cardiac myocytes. Regulation of L–arginine realisation that transport of pregnancy-associated diseases, such transport and NO production by CAT-1, CAT-2A, and CAT-2B. J Biol Chem 271, 11694-11702. L–arginine may be more complex as gestational diabetes, intrauterine than the initial “one-protein-one growth retardation and pre­ Wileman SM, Mann GE, Pearson JD, Baydoun AR (2003). Role of L-citrulline transport in nitric oxide synthesis in rat aortic smooth transport activity” paradigm, and eclampsia, can induce phenotypic muscle cells activated with LPS and interferon-γ. Br JPharmacol (in raise the question of the specific changes in the fetal vasculature which press).

FlexPDE PDE Solutions Inc has released its limited Student Version of FlexPDE, with complete documentation, free to all. FlexPDE is the unlimited equation-driven finite element solution environment in use in hundreds of corporations and universities around the world. It accepts as input coupled partial differential equations which may be linear or non­ linear, static or time dependent, from the simple Poison’s equation to Maxwell’s equation to highly complex coupled equations presented in a convenient scripting format. The student version has the full 2D and 3D capability of the professional version, limited only in the size of the finite element mesh and number of simultaneous equations (5). Further details from: www.pdesolutions.com 16 PN FEATURES

Not for giant axons only Pictures in the skin. Insights into fundamental functions from familiarity with the whole by Andrew Packard

It is not just for ethical and legal ‘octopus car’ when an anatomy reasons that most laboratories have student at the University of Toronto. abandoned the whole animal His faithful water-colours of approach to physiology. So perhaps I octopuses placed in this device in have been unusually lucky that my front of the marine biological station squids have still to be closed off on of Bermuda (Figure 1a,b) are the far side of the animal house door amongst the first attempts to classify in the name of tidiness and division the patterns of cephalopod molluscs Andrew Packard of labour. That I am able to practise (Cowdry 1911). Commuting between the art that served our predecessors Plymouth, Oxford, London and for hundreds of years: feeding, Naples in search of cuttlefish and caring, and generally getting to know octopuses, J.Z.Young, William each experimental individual: part of Holmes and Brian Boycott added to a procedure I have called the catalogue over the years. ontophysiology. For with (Young’s drawing of the male of a cephalopods, where colour is local species displaying to a female, concerned (Packard, 1995 for spotted while snorkelling between summary), one can follow activity sessions of external examining in simultaneously at the behavioural Singapore, is one of the few records and at intermediate levels down to of octopus courtship). So when Geoff the cellular. It is simply a matter of Sanders,Young’s psychology appropriate magnification – and of assistant in Naples, walked into my attitude. office with an armful of notes on the Figure 1a (above) and 1b (below) from Cowdry (1911) various postures and patterns The field is wide open and the observed during training experiments, intellectual rewards of letting the he was unknowingly continuing the animal tell its own story are great. tradition of noting down – and sketching – any new natural Access to brain functions behaviours seen during the course of through the systematics of experiments on quite different things. colour: the whole informs the parts Our job was to fill the gaps in the Edmund V.Cowdry (1888-1975), is ethological description and better known for his contributions to classification, and to parse the medicine than for constructing an patterns. Boycott had obtained

‘It is hard to believe that the sudden bleaching which occurs when the animal is poked with a stick is purely passive, and results, simply, from the elasticity of the walls of the chromatophores. Similarly, [with] the abrupt appearance of the long white stripes [Fig.1b right]… the possibility remains that the bleaching may be fundamentally passive and result from the inhibition of the impulses passing from the central nervous system to the chromatophores; but if this is the case we should have to assume that in the normal light gray coloration of the resting animal [Fig.1a upper left] the chromatophores are continually receiving impulses from the brain and that consequently the radial muscles are always in action, for we meet with a still lighter coloration as illustrated in [Fig.1a lower right]… The conclusion is therefore justified that, although the anatomical findings seem to show conclusively that the diminution in size of the chromatophores is purely passive and results from the elasticity of their walls, still close observation indicates that this may not be the case.’ Figure 2. Squid swimming in holding tank two days after cutting the pallial nerve (on near side) Cowdry (1911) FEATURES PN 17

preparation behaves very differently the nerve had never been cut – or as from, and much less reliably than, the if those normal patterns were also animal in its entirety. myogenic!

Unilateral denervation… Subsequently (four to eight days Although something of the wonder is depending on temperature) DDSS now lost to us, the Belgian gives way to coherent but irregular physiologist Léon Fredericq waves of twitch contractions (1851–1935) – who also was a propagating at ~1 cm/s throughout talented water-colourist (!) – the denervated territory - sign that discovered that when he reached nerve degeneration is complete. Like through the breathing aperture of an the tonic configurations, which can octopus to cut the pallial nerve on be regarded as slow or standing Figure 3. Different muscle contractile states signalled one side, half of the mantle waves of contractile state, these fast by the shapes of spots (Loligo vulgaris dorsal mantle 1 post mortem) (approx. x8 natural size) immediately went pale. The same waves exhibit chaotic dynamics. approach was used by Sanders and Young (1978) to very good effect in a Development the key to centrally induced expressions of rarely quoted study of pattern understanding coupled colour by electrical stimulation of regeneration. ensembles motor centres in the brain, and Fortunately, there are some simple before him Enrico Sereni (Young’s The paling of the skin following the rules for reducing the complexity of mentor when he was Oxford scholar initial cut does not last, however. At the picture at this stage, when at Naples) had tried pharmacological two days, as the mixed pallial nerve everything seems to be stimulation: a route later adopted by degenerates and denervation communicating with everything else. J.B.Messenger and colleagues. It was supersensitivity develops in the In cephalopods, as if their other gifts a short step to discover that the chromatophore muscles, the operated to the experimenter were not enough, irreducible (parsed) components of side gradually becomes dark brown the ontogenetic history of each the patterns corresponded to hard­ (compare Fig. 2). chromatophore organ is encoded in wired units in brain and skin which its position, in its size and in its could be topically stimulated with an ... and the myogenic signs colour (largest-darkest oldest, exploring electrode. that result smallest-lightest youngest) (Fig.5). Chromatophores (spots) are much At which point I naturally turned to larger in squids than in octopuses. With this knowledge, it takes only a the isolated skin, only to find – lesson The skin receives oxygen directly few seconds of the hundreds of hours number one – that the isolated through a surface of exceptionally of videorecordings of myogenic good optical quality, so that automaticity to realize that waves individual and collective signals tend to run selectively through generated by muscular tension on the yellow, orange, red, and brown spots spots can be recorded at relatively (of several sizes) lying in closely high resolution (Fig. 3) and for many superimposed networks. Within any hours (even days) following brain one network, connectivity (measured death. The tonic darkening of as probability of transmission of denervation supersensitivity (DDSS) contractile state) is normally 100%. is best seen when the rest of the Between colour classes it is animal is pale (Fig. 2 & 4c). Each differential.2 spot in these configurations has a round profile, roundness resulting I have given the name homeotaxy to from equal and synchronous the observed conformity of behaviour contraction of most (or all) of the 20 among elements of a given or so radial muscle fibres supplying developmental class when freed from any given chromatophore. These nervous control. It persists for as muscle fibres are coupled and their long as the skin remains alive. Is syntony and synchrony are myogenic. homeotaxy (Greek: same arrangement, or peer conformity to Figure 4a-c. Unstable configurations of myogenic Nevertheless, the configurations are give it an English name) a activity on the flank of a squid (highlighted) three days remarkably similar to patterns also after nerve section. Colouration of the rest of the body characteristic of waves propagating is driven by the brain seen on the intact side (Fig. 4b), as if through other coupled ensembles? 18 PN FEATURES

Complementary roles of none has ever been found. After spots in pattern generation… carefully comparing the colour of a Recently, squids have helped resolve pale octopus on a sandy ground and a problem that had plagued me for when ‘frightened’ (a pattern now decades. One class of pattern – in known as dymantic, or deimatic) the Nature as in Art – consists of both young Cowdry concluded that there figure and ground. The tattered bar was some form of inhibition: though that appears across the front of the not necessarily nervous (see Box p.16). mantle when a squid is hiding near the bottom of the tank (Fig. 6) is one How active, rather than passive, such feature (F). It behaves more or relaxation of chromatophores is less like classical motor units being achieved is still not clear. But the generated by twitches and tetani that whiteness of contrast – and of the expand certain dark spots. Increases ‘frightened’ octopus – can be in frequency of firing increase both simulated by subcutaneously injected Figure 6. Tranverse bar feature (F) of the cryptic the sizes of individual spots and the serotonin and by the nitric oxide pose adopted by Loligo. numbers of spots responding: a donor DEANO.3 The reaction process of spatial recruitment. Many propagates as a slow wave of of these spots have polygonal profiles relaxation and is stronger in in close up view (Fig. 6): the shape denervated than in innervated skin. telling which of the 20-25 muscle fibres surrounding each spot are … mediated by reciprocal developing tension. However, the inhibition between muscle many featureless uniform and graded fibres? colours in the repertoire of squids, Generation of features (F) against a which also furnish the ground (G) to clear ground (G) through opponent these bars, are not organised in clear­ processing need not in principle Figure 7. Relaxation of ‘caught’ profiles (A,B) in cut motor units. They are built up of involve nerves. One piece of evidence response to a brief seawater pulse (*) induces round spots – like the myogenically for its occurring as reciprocal phasic/tonic contractions in neighbouring spots (C,D). inhibition between different muscle Video-frame traces from Packard, 2002). (Loligo expanded spots encountered in vulgaris six hours post mortem) denervated skin. fibres is shown in Figure 7 presented at last year’s LiverpooI meeting References Opponent processing for the (Packard, 2002). I have since found Cowdry EV (1911). The colour changes of Octopus vulgaris Lmk. perception of contrast – necessary that the phenomenon, regularly seen Contributions from the Bermuda Biological Station for Research No. 22 and from the University of Toronto Studies. Biological Series, no. also for the discrimination of figure post mortem when the nerve has died 10. and ground – occurs early on in the or become anoxic, also occurs in the Packard A (1995). Organization of cephalopod chromatophore vertebrate visual pathway, classically operated half of a long-term systems: a neuromuscular image-generator. In Cephalopod through lateral inhibition. Contrast is unilaterally denervated mantle, i.e. in Neurobiology, eds. Abbott NJ, Williamson R & Maddock L, pp.331­ 368. Oxford University Press, Oxford. generated in the skin of octopuses, by the total absence of innervation. what appears to be lateral inhibition, Packard A (2002) Myo-muscular interactions: evidence for reciprocal inhibition between classes of muscle fibre. J. Physiol 543P, 104P. in situations of behavioural conflict If reciprocity is occurring between and as a major component of two muscle fibre types – either Sanders GD & Young JZ (1978). Reappearance of specific colour patterns after nerve regeneration in Octopus. Proc Roy Soc Lond camouflage patterns (Packard, 1995). directly or indirectly through an 186, 1-11. There has long been an argument interstitial cell layer – this would be a whether chromatophore muscle fibres new finding for muscle generally. It receive inhibitory innervation, though would make sense. Most visceral and other kinds of muscle in the animal Notes kingdom is in blocks that require 1 An exhaustive description of these waves requires video clips and has never been published. Some may be consulted on relaxation of muscle in some http://www.gfai.de/www_open/perspg/g_heinz/biomodel/squids/squid directions while those in the s.htm others on CD from the author. orthogonal are contracting. 2 Fast waves can be reversibly interrupted by topically applied Fundamental properties such as this heptanol (which is both anaesthetic and gap junction blocker). RF frequencies from a mobile ‘phone interfere with their generation. For have not evolved just for generating an eye-opening introduction to mechanism(s) that might be involved pretty pictures in the skin. in these (usually hidden) kinds of horizontal conduction, I recommend the review of Ho and Knight (Ho M-W & Knight DP (1998). The acupuncture system and the liquid crystalline collagen Andrew Packard fibres of the connective tissues Am J Chin Med 26(3-4), 251- 263. Stazione Zoologica ‘Anton Dohrn’, Naples, Italy 3 With thanks to Anna Palumbo. Figure 5. Fully retracted spots in a living Loligo. [email protected] Two colour networks indicated (5,7) FEATURES PN 19

Colour and form in the cortex Descriptions of primate visual cortex suggest that object’s colour and orientation of its contours are analyzed by independent, anatomically segregated neural populations. Recent results, however, show that cortical neurons can simultaneously code for both attributes. Cortical neurons, as Daniel Kiper explains, are thus ideally suited to analyze real scenes, where luminance- and coloured-defined contours are highly correlated

mysterious. Neuroscientists disagree orientation remains segregated within on the nature of the object’s V1, and through most of extrastriate representation in the cortex. cortex as well. This scheme implies Since the pioneering work of Nobel the existence of a later processing laureates D. Hubel and T. Wiesel stage in which information about an (Hubel & Wiesel, 1968), it is well object’s visual attributes converge to established that cortical neurons can yield a coherent, unified percept. The perform operations that earlier level ‘segregated’ scheme has received Daniel Kiper neurons cannot. In particular, most indirect support from the discovery individual cortical neurons are of functional streams in extrastriate When a human observer looks at an sensitive to the orientation of the cortical visual areas, with one stream object, perception of the object is object’s contours: a cell excited by a responsible for object localization elicited by the activity of numerous vertical contour will remain silent (the ‘where’ stream), the other neuronal populations. Most visual when seeing a horizontal contour, concerned with object identification neuroscientists today would agree on and vice-versa. The orientation (the ‘what’ stream) (Ungerleider & the neuronal events occurring in the selectivity of cortical neurons is Mishkin, 1982). The functional first stages of the visual system. The thought to be crucial for the distinction between cells within and light reflected from the object’s perception of form, a very important without the V1 CO-blobs is thought surface reaches the observer’s eyes, cue for object identification. In the to be maintained in the extrastriate where it is transformed into electrical cortex, the object’s colour is not functional streams. Some results are signals by the photoreceptors of the represented solely by the two distinct at odd with this proposal. retina. In daylight, three classes of channels (red-green and blue-yellow) cone photoreceptors respond described above, but by a population Quantitative studies of V1 receptive differentially to the wavelength of cells with a homogeneous field properties failed to find a composition of the incoming light, distribution of preferred colors. An segregation of function between cells thereby providing the physiological obvious question is to determine within and without the CO-blobs. basis for our trichromatic color whether the same cortical neurons They found many V1 cells selective vision system. After processing by the signal simultaneously the orientation for both colour and orientation, and retinal network, the signals of the contours and the object’s little correspondence between their representing the object are sent colour, or whether these tasks are distribution within V1 and the through the optic nerves towards the carried out by different populations location of the CO-blobs (Leventhal lateral geniculate nucleus (LGN) of of cortical neurons. Surprisingly, this et al. 1995. Similarly, in V2, the the thalamus. The retinal ganglion simple question has been the matter original proposal that color and form cells and LGN neurons represent the of intense debate in the last decades. are treated by segregated neuronal object’s physical properties in populations, also corresponding to roughly the same way: a population On the one hand, a number of distinct CO-compartments, has also of cells sensitive to local luminance researchers reported that colour been challenged (Gegenfurtner et al. variations signals the object’s selective cells in primate V1 are not 1996). Many reasons have been contours, while the object’s colour is orientation selective, and vice-versa invoked to account for these represented in two distinct channels: (Livingstone & Hubel, 1988; Shipp & discrepancies. They imply the one sensitive to red-green Zeki, 2002). Furthermore, these following requirements for any study modulations, the other to blue-yellow reports proposed that colour that aims at resolving this issue. (Derrington er al. 1984). Thus, in the selective, unoriented cells are found retina and LGN, signals coding for in clusters, corresponding to patches Clearly, any conclusion drawn from the object’s physical attributes are of tissue that stain for the data obtained on small samples of treated by separate, distinct neuronal mitochondrial enzyme cytochrome neurons will not be conclusive. A populations. Upon reaching the oxidase (CO), the so-called CO­ large sample of V1 and V2 cells is primary visual cortex (V1, striate blobs. According to that scheme, necessary to resolve the issue. cortex), the fate of the signals is more information about colour and Furthermore, functional properties of 20 PN FEATURES cells are best assessed in an awake demonstrate that many colour physical attributes of the stimuli used animal, because anesthesia can alter selective cells are orientation in the laboratory. the response properties of neurons, selective, and that non-oriented cells particularly in extrastriate cortex. can also be unselective for colour. Daniel C. Kiper Finally, quantitative methods must Institute of Neuroinformatics, University and Swiss be used to measure the cells’ These results demonstrate that the Federal Institute of Technology of Zurich properties and classify them into physical attributes of an object are functional classes. Qualitative not always treated by distinct classification of cells is difficult even neuronal populations. Instead, visual References for experienced researchers, and has neurons are concerned by the Derrington AM, Krauskopf J, Lennie P. (1984). Chromatic proven quite unreliable. These features most useful to detect and mechanisms in the lateral geniculate nucleus of macaque. J. Physiol. 357, 241-265 conditions were all met by a recent identify objects in a natural Friedman, S.H. Zhou, H, von der Heydt R. (2003). The coding of study by Friedman et al. (2003). They environment. Object borders are uniform colour figures in monkey visual cortex. Journal of Physiology. 548.2, 593-613, recorded the activity of cells in important such features and they are, awake, behaving monkeys, and used in most normal conditions, defined Gegenfurtner KR , Kiper DC, Fenstemaker, SB (1996). Processing of color, form and motion in macaque area V2. Visual Neuroscience 13, quantitative methods to characterize simultaneously by both a luminance 161-172. each cell. They collected data from a and a color gradient. It is therefore Hubel DH, Wiesel TN (1968). Receptive fields and functional large number of V1 (425) and V2 not surprising that the primate visual architecture of monkey striate cortex. J. Physiol. 195:215-43. (417) neurons. They computed system evolved neurons specialized Leventhal AG, Thompson KG, Liu, D, Zhou Y, Ault SJ (1995). indices to quantify each cell’s for the detection of borders Concomitant sensitivity to orientation, direction, and color of cells in selectivity for colour and orientation simultaneously defined by these two layers 2,3 and 4 of monkey striate cortex. Journal of Neuroscience 15, 1808-1818. and studied the correlation between attributes. These results add to the these indices. If colour and growing literature showing that the Livingstone MS, Hubel DH (1988). Segregation of form, color, movement, and depth: anatomy, physiology, and perception. Science orientation were treated by properties of natural images 240, 740-749. independent, distinct populations of determine the receptive field Shipp S, Zeki S. (2002). The functional organization of area V2: neurons, one should observe a properties of visual neurons to a Specialization across stripes and layers. Visual Neuroscience 19, negative correlation between large extent. In other words, the 187-210. selectivity for color and orientation. lesson for neuroscientists is that to Ungerleider LG, Mishkin M. (1982). Two cortical visual systems. In Their results clearly show that no understand the brain, one should Analysis of Visual Behavior, ed. DJ Ingle, MA Goodale, RJW Mansfeld, Cambridge, MA: MIT Press such correlation exists for any of the focus on the tasks that the brain has indices they used. Their results to solve, and not solely on the IMAGES OF PHYSIOLOGY PN 21

Images of physiology To launch a new series of physiological pictures, Thelma Lovick suggests images which might reflect our discipline in its broadest sense

Send us your images of physiology! The net will be cast widely. And we need your help. So if you have a stunning confocal image or original trace, let us show it! If you have a photo of an eminent physiologist from bygone years that might be of interest, or even one from the present day, we’d like that too. When out of the lab, some physiologists do the most amazing things - for example see the lady physiologists below! If you have made an ingenious bit of kit

or you’ve found something intriguing in the back of a cupboard and you don’t know what it does, let us see it. It’s all about sharing your

Image design: Bambrook Terry experiences! Physiology can be viewed from many perspectives: think of the beauty of Send your images for inclusion, ideas an attractive hypothesis backed up by etc and comments on this feature to elegant experiments and presented in the Physiology News editorial office or I.M. Sechenov (1829-1905) email the Executive Editor at a lucid manner from the lecture A visionary Russian scientist, Ivan M. theatre podium by a master. Cringe [email protected] or Thelma Lovick at [email protected] Sechenov was one of the first at the tortured writings of an physiologists to tackle the nature of undergraduate doomed never to ‘psychical’ activity. He asserted that grasp fully the subject. Re-live the the brain, like other organs, was long hours in the lab that sometimes governed by physiological laws and culminate in a real advance but so could be subjected to objective often lead to frustration as experimental analysis. He proposed equipment fails or that brilliant idea Do you recognise these lady that the principal forms of just didn’t turn out to be quite that physiologists (below), captured here psychological processes could be good in practice. outside their normal laboratory regarded as reflex events, in the environment? Prizes go to the first broadest sense. His revolutionary and Then there are the physiologists three readers to submit correct highly controversial thesis was, after themselves. Some are truly answers to the Executive Editor: some difficulty, published in inspirational, others are downright [email protected] Meditsinsky Vestnik in1863 under the boring but most are good in parts. title Reflexes of the Brain. Its original We all have something to contribute. Impact factor: scary title An attempt to establish the Then there is the perception of Physiological Basis of Psychical physiologists by the general public: as Processes had previously been rejected boffins in white coats, deranged by the censor. torturers of animals or, just possibly, scientists dedicated to understanding A contemporary of Darwin and an how the body works and what goes inspiration to Pavlov, Sechenov wrong if it malfunctions. deserves more recognition by Western physiologists. The English translation Images of Physiology is a new feature for Physiology of his book, published in 1965 by the News in which we hope to MIT Press, is still worth a read today. reflect our discipline in its broadest sense and largely Impact factor: inspirational in image form 22 PN IMAGES OF PHYSIOLOGY

The camera lucida One of those great British inventions, the camera lucida was invented in 1807 by Dr Wiliam Wollaston as an aid to drawing for artists. But strapped to a microscope, this simple little gadget was soon taken up by physiologists and anatomists and for the first time, enabled them to produce high quality permanent images of objects viewed down the microscope. Nearly 200 years later, camera lucida remains a useful tool. It is still used for example, by neurophysiologists to reveal the morphological characteristics of neurones whose functional electrophysiological properties have been characterised by intracellular recording techniques. Left: Golgi-stained cells in lamina IV of the motor cortex as seen by Ramon y Cajal. Right: Almost 100 years later a not dissimilar image of a pair of cortical neurones visualised after filling with biocytin. Dual intracellular recordings The beauty of it: so simple, never from this pair indicated that the interneurone (soma and dendrites in black and axonal arbour in red) was coupled to the pyramidal neurone (soma and dendrites in blue, axon not shown) via a single synaptic connection (arrow), breaks down and running costs are which was revealed in the EM. From Thomson et al (1996). J Physiol 496, 81 - 102 unimaginably low - requires pencil and paper only.

Impact factor: 10/10

Where would we be today without fluorescent calcium sensitive dyes? Arguably the most powerful tool available for probing the kinetics of intracellular ion movement, many stunning and aesthetically pleasing images have been generated. But perhaps one of the most intellectually satisfying aspects of calcium imaging, thanks to advances in confocal microscope technology and image analysis software (see left), is the ability to portray calcium movements in time and space, bringing a new dimension to understanding intracellular and intercellular signalling processes. Evolution of calcium signal in cortical astrocytes loaded with rhod-2 in response to stimulation with ATP. Intensity profile along a line selected along the axis of a cell is displayed as a surface plot. A relatively fast and transient increase in [Ca++] in over the nucleus (*) contrasts with the slower and sustained widespread ncrease which Impact factor: picture worth a develops over the mitochondria as the signal spreads. Image from Duchen (1999) J Physiol 516, 1-17 thousand words AFFILIATE NEWS PN 23

The art of scientific endeavour Keri Page visits Four Plus: Writing DNA, part of the Wellcome Trust’s DNA50 celebrations

The use of unusual media is common combination of video and a hand­ to many of the exhibits. The Secret scribbled diary of sorts, the piece of Life by Jessica Curry and Dan draws links between Franklin’s career Pinchbeck, for example, is a multi­ path, her crystallography and the sensory DNA-inspired sculpture (Fig. process of innovation. The 1). Complete with ‘music’ that is nonsensical detail and tortuous apparently dictated by the rules that description of the artist’s ‘journey’, govern DNA coding. This audio however, hints of the mundane visual experience centres around a repetition that pervades the lives of white model, onto which Rosalind practising research scientists. Keri Page Franklin’s X-ray diffraction As scientists we take great pains to be photographs and portrait are The full exhibition is spread over five objective, detached and unwavering projected. Like the complexity of the floors, and across two Wellcome in our dedication to Popperian music, the shape of the sculpture is buildings. With map in hand I falsifiability. For artists, the opposite elusive. Because of its large size and negotiated the maze of exhibits, only is true. When a masterpiece is created close proximity, the shape cannot be to find that by the end, not only had in passion and doused in personal fully appreciated, except from above I developed a headache but I had projection, there need not be one - an intentionally awkward position traversed five floors, in a helical truth, and work is open to from which to view the display. All fashion, in search of titbits. Imitating interpretation. While science is together, these absurdities make one the flavour of discovery, the designed to be devoid of human realise how palpable the discovery excursion was far from a walk in the contamination, art is the very must have felt to Franklin – so close park. epitome of the opposite ingredient, and yet so far. and may be an extension of oneself. Some of the Four Plus: Writing Together one might expect these two In this way the exhibition speaks DNA exhibition features the archives opposites would mix like oil and truths, not only about the discovery of Francis Crick. Purchased by the water, but this does not appear to be of DNA but also about the nature of Wellcome Library in 2001, the papers the case. the scientific research process as a will soon be fully accessible to library whole. This sentiment is echoed by users. A sketch drawn by Crick Indeed, it seems we share a common Richard Dedomenici’s tribute to himself shows the way the image of drive: to describe our world and Franklin, ‘The Rosalind Project.’ A DNA was initially conceived (Fig. 2). increase our understanding as best we know how. A fusion of art and science may not be commensalism, but a fresh symbiosis, in which science is infected with inspiration, awareness and hedonism, and art with new images and the taste of a dissimilar psychology. Certainly this collaboration is encouraged by the Wellcome Trust and flaunted in their most recent exhibition, Four Plus: Writing DNA, which is part of the Trust’s DNA50 celebrations.

Displaying the work of 10 varied artists, the exhibition explores not only images of DNA but the lives of those historic figures who were integral to its elucidation, the process © The Trust Wellcome of research and discovery, and also Figure 1. Jesicca Curry and Dan Pinchbeck. The Secret of Life 2003. the implications of this molecule for Mixed media installation with perspex, digital sound, animation and video projection. Dimensions variable how people today see ‘life.’ 24 PN AFFILIATE NEWS

Reassuringly human and abstract, is influenced by zero gravity (Kitsou the drawings, in combination with Dubois and Imperial College annotated manuscripts of the original Biodynamics Group). These are just Nature paper of 25 April 1953, make a few of the developments born of the discovery of DNA feel the Wellcome Trust’s past remarkably more tangible and competitions and exhibitions. fallible. This personal touch is Perhaps together scientists and artists cemented by Penny McCarthy’s might continue to explore the space drawing of the Watson and Crick between these two disciplines. paper. The painstaking effort and concentration that would have been Scientists themselves, however, are required to create this pencil drawn not without their own sense of replica – of actual size, in some way aesthetic beauty. Contemporary mimics the hard work behind the © The Trust Wellcome science provides us with fabulous new print. For information about the tools and imaging techniques, Figure 2. Francis Crick, sketch (pencil) other works at the exhibition and the of double helix (1953) capable of telling complex stories artists involved see: about biology. Visualising cutting www.wellcome.ac.uk/en/1/awtprerel0 inspired by DNA, genetics or edge concepts about our world and 103n281.html heredity. our bodies in this way is increasingly viewed as having artistic merit. If you An amalgamation of art and science Self-indulgence is unlikely to be the are feeling creative or are proud of an can obviously be entertaining, but only outcome of science-inspired art image you have created that reflects how does each side of the for researchers. We might also see the our discipline, why not jump on the engagement benefit? The Wellcome emergence of art-inspired science. science-art bandwagon and submit Trust’s TwoTen Gallery was Since artistic interpretation is a your ideas to Images of physiology established in 1995 with the main aim product of a self-awareness and (see p. 21).Who knows where this of engaging public interest in science. psychological complexity unique to new kind of experimentation will ‘In order to raise awareness of our species, new lines of scientific take us? medical, ethical and social enquiry might be drawn from looking Keri Page implications of biomedical science, more intimately at artworks. Benefits one of our strategies is to use the Department of Zoology have already been drawn from closer University of Cambridge mechanisms of engagement via the scrutiny of how self-portraits are visual, literary and performing arts,’ affected by developing Alzheimer’s says Denna Jones, Curator at the (William Utermohlen), how amputees Four Plus: Writing DNA continues at Wellcome TwoTen Gallery. The visualise their phantom limbs (Alexa the TwoTen Gallery and the Wellcome gallery puts on several exhibitions a Wright), of hand-eye co-ordination Building, London, until 29 August year simply to ‘explore the during portrait drawing (Humphrey 2003. possibilities’ of sci-art, says Jones. Ocean and John Tchalenko), and Public understanding is something how motor control in choreography science desperately needs. Perhaps we should embrace the emotive and aesthetic side of science in order to help ourselves.

The Wellcome Trust further facilitates scientific art in their schemes and competitions. As well as commissioning two six-month artist residencies a year, the Trust annually runs a sciart award scheme. This scheme invested £1million in art­ science projects in 2002 alone (Website). A competition for amateur photographers, run by both the Wellcome Trust and BBC, is also currently underway – deadline 30 June, 2003. Entitled ‘Imagine’ the competition invites photographs LETTERS TO THE EDITOR PN 25

while telling me the story. That was the day before going to Martin sessions should certainly have read Place as a tourist so the connection escaped me. The outback experience the communications carefully As I recall, the closest we got to fermented grape juice was a flat beforehand. It is their role to white in a paper cup which I promptly spilt down my trousers. Dear Editor, Perhaps Max did slip in some centrally acting factor after all. supervise the smooth running of the In Ashmore’s very amusing account session, keep the speakers to time, of his visit to Oz (Physiology News, direct questions to the speaker, number 51) he makes the statement identify the person asking the that the celebrated photograph of Abstracts – to be or not to question, and most of all to enliven Eccles, Katz and Kuffler (reproduced and stimulate discussion. They in From Neuron to Brain) was taken be? cannot carry out this last task if they in the main quadrangle of Sydney have not read the papers beforehand University, according to Max Dear Editor, and so will find it difficult to engage Bennett. This photograph was taken In Physiology News, number 51, Ann the audience. in Martin Place in the heart of Silver writes about Abstracts. Sydney. Martin Place is the site of Unfortunately, unlike her I do not This last point, engagement of the the Cenotaph and so corresponds to have a long series of copies of the audience, is often not uppermost in Whitehall in London. It is now Society’s magazine since I have not the minds of the presenters at the closed to vehicular traffic but in received them for many years. recent meetings I have attended. Far 1941, when the photograph was What Ann Silver writes about too often there is an extraordinarily taken, you can see cars parked on abstracts makes a great deal of sense. bizarre use of colour simply because both sides of the road and the old Microsoft have made it available, not General Post Office in the In particular the loss of pre­ because colour helps to convey background. The trio are walking circulation of programmes seems to information. Coupled with that is the uphill towards their laboratory in the me to be a mistake. I do know about imposition on the audience of far too Kanematsu Institute in Sydney the internet address but the Society, many slides. In a two or three hour Hospital. It is believed that they had in common with so many other session it is quite impossible to take come from Sydney University where organisations, is throwing the onus in 10 slides every 15 minutes, one of them (probably Eccles) had and the cost onto their customers or especially when the axes are not given a lecture (on the endplate members. This may matter little to defined nor are the units given by the potential?). In those days it was members who are employed in speaker and the histograms change customary for commercial universities and institutes since the colour without warning. The blame photographers to take shots of costs of computer usage are hidden for this retrogressive behaviour must passers-by at random and hand them to them personally. That is to say lie with supervisors who do not train a card with a reference number on it. purchase of a computer, rental of their graduate students and post-docs Anyone who was interested could telephone line, subscription to an to discipline themselves. All this check the photo later and purchase it ISP, printing costs including ink means that the speakers are talking if they liked it. The anonymous cartridges, and paper, and so on. to themselves or maybe one or two photographer who took this photo This means that the retired members friends whilst other members of the probably never realized how famous who pay for all these things Society are not engaged. Do the his shot had become. Max Bennett themselves are those that are speakers practice their assures me he did not give any dud penalised. There could be a view that communication in front of members information to Ashmore. It is this does not matter since they are of their department who are not reasonable to conclude that either unlikely to be active nor to working in their group ? one or both of them had been over­ contribute much to discussion at indulging in the fermented grape juice meetings. But the effect is to tend to A failure to communicate clearly is a which is so popular with Poms down exclude them even if they wish to stay pity, for some people go to meetings under. a part of the Society and so to lose in order to learn about fields new to their experience of science, of life, them. In addition those who produce Liam Burke and of their willingness to ask simple these awful communications will not Emeritus Professor of Physiology questions. University of Sydney, Australia endear themselves to members of the Society who may have jobs to offer. I do not know what the Society now Jonathan Ashmore replies: does about ensuring that Chair­ Tim Biscoe Many thanks for the correction about the EKK photo in my men/women of sessions have the Emeritus Professor of Physiology lightweight article in Physiology News. The facts are much more interesting than fiction. Of course, had I done my research properly, I abstracts well beforehand, maybe University College London should have realised that the cars in the photo could not possibly they also are expected to download have been in the University of Sydney. them, but do they? This is important I hope you will mollify Max who certainly did not give me dud because Chair-men/women of information - I remember him gesturing in the direction of the quad 26 PN SOCIETY NEWS

expenditure, conducted in 2002. The were introduced. It is envisaged that Review of Society grants aim was not to reduce spend, in fact by consolidating the schemes, there New grant schemes for it is hoped that it will increase with will be greater transparency (all the larger income stream owing to applications will be viewed side by Members and Affiliates the change of publisher. However, side), and also that no Member will As of 1 August, 2003 the Dale and there were some inconsistencies with be disadvantaged purely on the Rushton Scheme, International the schemes that had evolved, and grounds of where they live. Priority Bursaries and International Meeting also a feeling that streamlining in all cases will be given to Travel Grants will be consolidated to administration would be helpful. Members/Affiliates applying for form one grant for Members, and the funds to attend Physiological Society Affiliate Travel Scheme, Affiliate Academic life has changed over the meetings, workshops or sponsored Home Meetings Scheme, last few years, and the Society’s events. International Bursaries and membership has altered in response. International Meeting Travel Grant Owing to greater use of the web and There are new two monthly deadlines will be consolidated to form one email, scientists increasingly for receipt of applications (published grant for Affiliates. There is now one collaborate with colleagues in far on p. 27). Please note that form available for Members and one flung places. There is a greater need applications cannot be considered for Affiliates, which can be accessed for scientists to move around the retrospectively. Deadlines will always from the website. Criteria and globe for collaborative visits and be published on the website. eligibility are also published on the meetings. There is also an web. Members and Affiliates are expectation that Society meetings will A final plea from the office. We try invited to apply for money to attend have a truly international flavour, to transfer as much money as and present at scientific conferences and that there is a need to support possible by BACS transfer. The most (including domestic and international scientists from developing countries common reason for delay in paying Physiological Society meetings, to attend our meetings. grants is incorrect bank details. sponsored meetings and symposia, Please double check that the account meetings of other societies), to visit The original grant schemes were numbers, etc. submitted are correct. another laboratory for collaborative developed based on the premise that research or to acquire new techniques most of our Members and Affiliates The new schemes will be trialled for or to attend a practical workshop or lived and worked in the UK and one year, and then reviewed. For training course. Guidelines and Republic of Ireland, and would questions concerning the review scoring criteria are published below. require money to travel overseas. please contact myself or Jamie Gould When a need for funding was at the office. These changes have resulted from a recognised which was not in the remit review of Society charitable of existing schemes, new schemes Maggie Leggett

Members Grant Applications

Scoring criteria 1. Active membership, or applicant in the process of applying 2. Benefit to applicant (development of research, career progression, opportunities for collaboration and networking) 3. Benefit to physiology 4. Benefit to Society 5. Other funding opportunities (including applications to other appropriate sources) 6. Breakdown of costs Guidelines 1. Members are invited to apply for travel grants: a) to attend and present* at a scientific conference (including domestic and international Physiological Society meetings, sponsored meetings and symposia, meetings of other societies and other international scientific meetings relevant to physiology). A copy of the abstract should be included. b) to visit another laboratory for collaborative research or to acquire new techniques c) to attend a practical workshop or training course. 2. Applications from Members not resident in the UK/Republic of Ireland to present at meetings of other societies, or for collaborative visits outside the UK and RoI, may be considered under exceptional circumstances. 3. Applications must be made before the intended travel date; retrospective applications will not be considered. 4. If you are in the process of applying for Membership, please include your address and date of application in a covering letter, together with a covering letter or email from a sponsor, preferably a current Member of the Society or your Head of Department. 5. Scoring criteria are published on our website. Looking at these might help you to make a successful application. 6. Please note that normally you will be eligible for one grant a year, up to the value of £600, although more may be available for lab visits and courses. 7. If you have any questions relating to the grant or membership application process, please contact Jamie Gould at: [email protected], telephone +44 (0)20 7269 5726.

* Presentations include invited lectures, oral and poster communications, or demonstrations. SOCIETY NEWS PN 27

Affiliate Grant Applications

Scoring criteria 1. Active Affiliate membership, or applicant in the process of applying 2. Benefit to applicant (development of research, career progression, opportunities for collaboration and networkin 3 Benefit to physiology 4. Benefit to the Society 5. Other funding opportunities (including applications to other appropriate sources) 6. Testimonial/letter of support from supervisor/Head of Department 7. If UK or RoI resident applying for overseas travel - evidence of presentation at a domestic meeting of the Society

Guidelines

1. Affiliates are invited to apply for travel grants a) to attend and present* at a scientific conference (including domestic and international meetings of the Physiological Society, meetings and symposia sponsored by the Society, meetings of other societies and other international scientific meetings relevant to physiology). Please include a copy of the abstract. Please note that the grant will not be awarded unless you are the presenting author. b) to visit another laboratory for collaborative research or to acquire new techniques c) to attend a practical workshop or training course. 2. Applications from Affiliates not resident in the UK/Republic of Ireland to present at meetings of other societies, or for collaborative visits outside the UK and Eire, may be considered under exceptional circumstances. 3. Applications must be made before the intended travel date; retrospective applications will not be considered. 4. Please note that in order to apply for travel expenses to non-Society meetings overseas, you should have presented* at a domestic Physiological Society meeting. Please include full details on the application form. 5. If you are in the process of applying for Affiliate Membership, please include your address and date of application in a covering letter. 6. Please include a covering letter or email from a sponsor, your supervisor or Head of Department, preferably a Member of the Society. 7. Scoring criteria are published on our website. Looking at these might help you to make a successful application. 8. Please note that normally you will be eligible for one grant a year, up to the value of £400, although more may be available for lab visits and courses. 9. If you have any questions relating to the grant or membership application process, please contact Jamie Gould at: [email protected], telephone +44 (0)20 7269 5726.

* Presentations include oral and poster communications, or demonstrations.

Grant Deadlines Society) and latterly Catherine welcome any interested Member who Joynson (Institute of Biology). In wishes to attend. The programme Affiliates Members April, the Physiological Society and registration form can be found (includes any applications from members wishing to apply for funds to Executive Committee took the on the education page of the website go to the relevant Society meeting) decision to second me one day a week (www.bsf.ac.uk), where further

31 August, 2003 (Cambridge) 30 September, 2003 for a year to assist in the areas of details of current Federation 31 October, 2003 30 November, 2003 public relations and education. One activities are also available. 31 December, 2003 (Glasgow) 31 January, 2004 29 February, 2004 (Cambridge) 31 March, 2004 of the activities I have been involved 30 April, 2004 (Cardiff) 31 May, 2004 in is the organisation of the Maggie Leggett 30 June, 2004 (Cork) 31 July, 2004 31 August, 2004 (King’s) 30 September, 2004 Federation’s first event, an Education 31 October, 2004 30 November, 2004 Colloquium, to be held on 6 October, 31 December, 2004 2003 in London. Hot Topics

Increasingly, when speaking to The 6th CHOP ‘Hot Topics’ meeting Biosciences Federation Members, concerns are expressed held in Manchester on 24 – 25 March regarding the levels of knowledge of (co-hosted by Arthur Weston) was The Federation has had an active their undergraduates when they the first joint meeting of the first few months. Recruiting members arrive at university. Changes in post­ Committees of Heads of and fund raising have been key, and 16 qualifications mean that Pharmacology and Physiology. And significant advances have been made universities are accepting students it was a timely meeting, with lots of in both areas. Replies to consultation with a broader range of AS and A2 discussion and debate about documents on subjects such as the levels. Unfortunately, in order to interdisciplinary work, addressing Higher Education White Paper, the achieve that extra breath, some depth both political and scientific issues. Forward Investment Strategy of the has been lost. In addition to this, MRC and teacher professionalism many institutions are still facing Professor Alan Cuthbert and the role of subject specialism recruitment problems and need to (Cambridge) provided a challenging have all been submitted. know how best to attract students start with a speech ‘from the heart’ and how to help them overcome asking us all to hold on to our Until the Federation achieves a firm obstacles when they arrive. This names, guard our courses and financial footing, it must rely on staff colloquium will explore some of these increase our profile with the general seconded from various societies to issues, bringing together academics, public. Speaking as a member of provide a secretariat. Hence in the teachers, and those that have both the Pharmacological and policy area there has been much conducted research in the area. The Physiological Societies, Alan activity, thanks to the excellent work colloquium is free and we would Cuthbert was well placed to give a of Mike Withnall (Biochemical

SOCIETY NEWS PN 29 perspective on the government white Heads of Pharmacology and taught to teach? The issue on debate paper and to raise concerns which Physiology returned to the was clear: ‘This house believes that this clearly signalled for our future. advantages of interdisciplinarity. requiring all university teachers to In a world of new challenge for have a teaching qualification will education, from widening So to a talk which could have been destroy the British University participation to top up fees, and new controversial and political. Slick and System’. To support the motion Ian challenges for science around new professional, articulate and precise, Naylor (Bradford) gave a tour technologies, from genomics to Nancy Rothwell gave firm through the history of education, proteomics, we needed to be attentive foundations to the formation of the from Voltaire (‘all styles are good to our departments. Alan Cuthbert Biosciences Federation. There was except boring’) to Memoir of a questioned the level of investment in no controversy as to the main theme, Thinking Radish by Peter Medewar new technologies – rather than to embrace and engage in an agenda (1986: ‘A dialogue to promote, leading to any enhanced drug for change, to grasp new exercise and enlarge the powers of discovery programme, the massive opportunities, with a united voice – the mind’). Ian’s support for the financial investment in the new whilst maintaining our identities. motion drew on personal experiences technologies coincided with a massive This is not to say that emotions did and concern for the product which reduction in the number of new drug not run high – but a ‘coming entered HE from the School system. candidates reaching the regulatory together’ is bound to create But does this mean we should not authorities. The pharmaceutical suspicions and heated debate. have formal pedagogical education? industry was calling for more hands­ on skills, for employees with in vivo The debating mood continued after Lorraine Stefani (Strathclyde) gave a technical knowledge. So, time to re­ lunch (fuelled by lots of lunchtime powerful outline for the need to think our research focus? Not networking and discussions around educate all academic staff in surprisingly, the discussion continued RAE funding, university mergers, pedagogical issues, to help them to well into the evening! and visions for the future – all very engage the new student mix in the therapeutic!). learning process, to encourage the After such provocative debate, the autonomous and independent following day could not have started The first topic of the afternoon was learner, to create reflective learners better. Roberto Solari (former Head the future of animal-based research (and teachers). Lorraine felt it was of Cell Biology at GlaxoWellcome) in the UK and how we should crucial to expose staff to the craft of gave a complex and professional talk address the 3Rs. Armed with a teaching, to give emphasis to the around the post-genomic era. The complimentary copy of ‘from guinea scholarly pursuit of teaching. All the emphasis on interdisciplinary work pig to computer mouse’, delegates pedagogy required for any person was excellent, and set the scene for were ready for debate. Bob Coombes committed to QA procedures was the remainder of the morning. But (FRAME) gave an elegant espoused by Lorraine, and the the talk also raised the issues of the presentation on sensible ways to audience listened! So, on to the previous evening. Pharmacologists tackling the 3Rs and Clare Stanford debate. and physiologists all recognised the (University College, London) gave us rapid advances made in the fields of insight into public perceptions of The pedagogical experts were genomics and proteomics; the what is or is not appropriate to harassed by those who were ‘insulted’ question for many was whether the develop as a medicine. There is no by Lorraine’s comments that one advances (and the promises for the doubt that as professionals we need needed to be taught the powers of future) lived up to the enormous to rehearse our PR since the level of reflection, different teaching styles, investment – person power and understanding of the public must be different assessment procedures. financial. No-one doubted the appreciated – we may see the medical Kathy Kane (Strathclyde) brought importance of the core science benefits of anti-obesity drugs, the calm to the storm by supporting knowledge which had evolved but treatment of drug dependency Lorraine’s logical pedagogical this needed strengthening to provide withdrawal or the very positive uses presentation and stance, but then a firm basis for scientific for Viagra, but the public may see outrage was expressed at the advancement and drug development. only the quality of life issues. ‘Be emphasis on ‘requirement’ for a prepared to defend the benefits of teaching qualification. It was a fun As Nancy Rothwell (Manchester) research’ was the message from two debate on a difficult subject. Whilst said, provided we work together to highly committed speakers. the writer believes everyone in the design studies with rigour then the room acknowledged the need for outcomes can be maximised. Again On to education per se, and the education of the teacher, the nature and again the discussions of the first second debate of the afternoon. of the formality of this provision was joint meeting of the Committee of Should we, as educationalists, be the dividing query – and the motion 30 PN SOCIETY NEWS was carried – despite the chair for the Sponsorship from the Physiological take part in organising Life Science afternoon, Ian McGrath (Glasgow) Society enabled myself and two other Careers’ Conferences for acknowledging that he was a convert affiliates to attend to represent the undergraduate and postgraduate to pedagogical education!! society. Our work was presented at a students. level accessible to non-scientists, Brian Furman (Chair, Committee of which in itself was an unusual This year the venues and dates are: Heads of Pharmacology) chaired a challenge and was well received by pharmacological/physiological biologists and non-specialists alike. King’s College, London morning and Ian McGrath (Chair, 1 November, 2003 Committee of Heads of Physiology) Almost 100 MPs expressed interest in steered the afternoon debates. A attending the receptions. truly interdisciplinary event which all Unfortunately, the timing of the UMIST, Manchester agreed should be the start of further event coincided with the final debate 15 November, 2003 sharing and collaboration. The best on the Iraq crisis but, nonetheless, a possible way to face change and significant number of MPs did find challenge ... together!! the time to visit the exhibition despite University of Cardiff more pressing political concerns. 29 November, 2003 Brenda Costall Though not the main objective Secretary, Committee of Heads of Pharmacology concern of these events, discussion of These conferences give students funding and the future of UK science information about career SET for Britain was inevitable - giving us the opportunities available to them after opportunity to raise concerns of the graduating. They are the only Poster presentations by upcoming generation of scientists and careers’ conferences targeted at life Britain’s top younger engineers regarding funding, career science students and are a must for scientists, engineers and prospects, research facilities and any student unsure of what path to take. Topics covered throughout the technologists at the House training, and above all, to discuss and hopefully influence government day include: research in universities of Commons, 17 March, 2003 policies of commitment to research and in large companies, careers in The 5th annual parliamentary for the future. These topics are clinical and biomedical science, presentation of British research and covered by the Commons’ Select teaching in schools, patent law, R&D concluded the events of this Committee for Science, as part of the careers outside the laboratory, year’s National Science Week. Two ‘Voice for the Future’ initiative. volunteer work abroad, job hunting receptions were held. The first, at and interviews, and science lunchtime, covered science, Overall this event was an interesting communication. We also hold engineering, medicine and technology occasion, allowing direct interaction curriculum vitae workshops which with a more specific theme of between younger researchers and MPs, give delegates a chance to receive nanotechnology being shown at a promoting the value of researchers and feedback on their current cv. separate reception in the evening. their work for the future. These events are held annually at the At each conference, many companies Lauren MacKenzie and universities are invited to take House of Commons and sponsored The Babraham Institute by GlaxoSmithKline. They aim to part in an exhibition. This gives the encourage dialogue between chance for undergraduates and Members of Parliament and Britain’s Careers conferences: where postgraduates to meet employees younger researchers. from these companies and get an does your future lie? insight into the work they do. These meetings also provided an opportunity for younger scientists to Each conference attracts around 300 exhibit their current research and undergraduates and postgraduates meet with their peers from a wide from Universities and research spectrum of science, medicine and institutes throughout the UK. technology. Some of the more topical At the end of each year the All undergraduate and postgraduate subjects covered at the lunch-time Physiological Society, along with life scientists are welcome to attend, reception included railway safety, other learned societies (Biochemical and find out where their future lies... urban air quality, biological weapon Society, British Pharmacological detection, military aircrew safety and Society, British Society for Sai Pathmanathan the relationship between speed Immunology, Institute of Biology, cameras and road traffic accident Society for Experimental Biology and statistics. Society for General Microbiology),

32 PN SOCIETY NEWS

On the 12 March, 2003 two sixth teachers were able to see students Sixth Form Workshops: form days sponsored by the apply their knowledge to top level Physiological Society took place in research and ask intelligent questions. Bristol and Chester Bristol and Chester. Many students who have attended The Faculty of Applied Science in the sixth form days in the past have University of the West of England progressed to study physiology or a held a practical hands-on workshop related subject at university. For for A-level Science students called many of them these sixth form days THE BRAIN-JUST USE IT! The were their first chance at seeing real event was part of Brain Awareness science in real laboratories. This is a Week and National Science Week. very powerful form of advertising for Schools from all over the South West the universities who organise the of England attended (with one school event, as well as better establishing travelling all the way from Cornwall). their links with local schools. At Chester College of Higher Education a set of Sport and Exercise Anyone wishing to organise a sixth Physiology workshops attracted form day next year, please contact: students from all over the North me on 020 7269 5727 West. Approximately 80 students ([email protected]). turned up to each event, although many last minute applicants had to Sai Pathmanathan be turned down due to lack of space, resulting in teachers requesting that more such events should be held. Free CDs

Each sixth form day consisted of a A generous grant from Pfizer has variety of lectures and workshops. enabled the Physiological Society and Topics included: electron microscopy, the British Pharmacological Society nerve conduction, pupillary reflexes, to offer departments of optical illusions, animal models of pharmacology and physiology a free stroke, enteric brains, the brain and CD about laboratory animal exercise, stress biology, anaesthesia, surgery and peri­ immunoassays, and even an advice operative care. These CDs are session about applying to university. produced by the University of Newcastle. The CDs have been Although the workshops were reviewed by one of our Members, sponsored by the Physiological who commended them and Society, much of the hard work and commented ‘They can be used to organisation was by Dr Stephen illustrate specific aspects of Gomez (Bristol) and Dr Graham anaesthesia and operative techniques, Bonwick (Chester). They both did a and to supplement other material. terrific job of making sure everything The material covered is appropriate ran smoothly, and that students were for anyone planning to start to carry entertained and attentive. Thanks out experiments on anaesthetised must go to all those who gave up animals, and also for scientists with their time to help run the events experience in such experiments who (Dave Patton, Carolyn Paul, Dave may need a quick update on current Lush, Priscilla Heard, Malcolm methods.’ Watson, Roy Pope, Richard Osbourne, Stuart Bruce-Low, John If you would like to receive a copy, Williams, Mary Cotterrell, Becky please contact Sarah-Jane Stagg at Kendall, and Sarah Andrew). the BPS Office ([email protected]). Supplies are limited, so copies will be Feedback from both workshops has distributed on a first come first Getting on your nerves! Nerve conduction practical been extremely positive with requests served basis. where students measured the conduction velocity of to run additional events. It was the ulnar nerve encouraging to see so many students Maggie Leggett take part in the workshops and the UNBELIEVABLE! PN 33

Of course, one should always treat poisonous substances with respect, and very poisonous ones with more respect still. But for everything else, not eating it or rubbing it in your eyes (common sense) is pretty much enough. After all, eating my dodgy chicken sandwich and its payload of Campylobacter will probably make you a lot sicker than accidentally inhaling a bit of acetone. Unfortunately, the fact that about half the chemicals on the shelf still have a COSHH sheet tends to blur the distinctions Safety farce between them, even when the distinctions are important. So the safety bureaucracy actually ends up making things less Here in the Cain laboratory we have just been subjected to safe. that annual joy, the safety inspection. The safety inspection is one of those occasions when you find out just Or take most of the GM Rules. Do these really concentrate how many friends you do – or don’t - have in the on the few things that are actually likely to be hazardous? I department. don’t think so. If they want to give you a pass, they can, by ignoring the Instead, they just create work. All cell culture waste has to odd dangling power lead, the computer with no side be treated as a Biohazard and autoclaved, in some cases panels, the heavy objects on high shelves (where the hell twice, before it can be burned. Every pipette tip, every else are you supposed to store anything?) and the bottle of plastic tube, every pair of gloves. Even the effluent perfusate glass-cleaning stuff that’s lost its label. (Danger! Alkaline from your patch-clamp rig. Hazard! Irritant!). In the old days this waste perfusate went down the sink. We Provided that (i) they don’t find the bottle of whisky you would mix it with bleach first to keep the lab fragrant and stashed behind the Qiagen catalogue, and (ii) you don’t hygienic, especially if we had been doing an experiment with have an incriminating week-old Tandoori chicken something toxic. Very conscientious, I used to think. sandwich in the fridge, you can usually just about get away But nowadays doing this is a no-no. Why? Because – shock with other stuff. But if they want to bust you, they can. horror - human cells might get into the waste water system. It’s a bit like traffic wardens. Remember parking on that Well, perhaps it has escaped the notice of the law-makers, single yellow line at precisely 6.32 p.m., a full two minutes but human cells go into the waste water system every time a after it was legal? And then the traffic warden ticketing human being does what comes naturally and answers the you, because their watch said it was 6.29 p.m.? (Of course, call of nature. Remember your excretory physiology? The a smart traffic warden is bound to have a watch that runs main pathways for daily iron loss from the body are ... yup, two or three minutes slow. Makes sense.) Anyway, you that’s right. ended up with a ticket. Which you had to pay. The difference is, in a lab we have to have a specially sealed The point being: you can’t beat them. They can always get floor, and the waste goes for autoclaving. In your you if they want to. bathroom, you just flush. And it’s the same with the safety people. There are enough If only one could just flush most of the safety bureaucracy. rules that they can always find you contravening at least a But no doubt it’s here to stay. Along with all the rest of the few of them. The question is whether they decide to enforce tons of regulatory paperwork that is slowly drowning the them all that particular day. public sector in Britain. So you had better pray that your Departmental Safety As a final aside, here is a little Safety Cautionary Tale. Officer is a reasonably normal human being. And not a A couple of months ago I spent 10 minutes writing out a rule-crazy zealot, or a person who missed his or her true COSHH form for 30% Hydrogen Peroxide. Oxidizing! calling as – what else - a traffic warden. Causes burns! Hazard! Of course, those who are really to blame are the civil Clearly highly lethal stuff, only available to qualified servants and legislators who made University laboratories scientists for use under the most carefully controlled subject to safety regulations, most of which were clearly laboratory conditions. designed for industrial workplaces occupied by people with less common sense than the average potted plant. Or alternatively: available in litre quantities in your local supermarket, where it sells as “Biodegradable Chlorine-Free Because, let’s face it, most of the rules are completely mad. Bleach”. For instance, although one no longer has to fill in a COSHH assessment for every chemical (which led Don’t worry though. It has a hazard sign on the label. It’s originally to such Kafka-esque classics as the COSHH just that no-one know what it means. Except for us assessment for sodium chloride) one still fills them in for scientists. ANY chemical deemed an “Irritant”. This includes such high-risk substances as calcium chloride, potassium Mark Cain chloride, and glycerol. 34 PN OBITUARIES

lecture, given in 1952 when he Bernard Katz was born and brought Bernard Katz became professor of Biophysics at up in Leipzig, so his native language 1911–2003 UCL, Katz expressed his gratitude to was German, though he was never a A. V. Hill ‘for all I have learnt, not German citizen. Bert Sakmann only as a pupil of a great master of relates that when BK first spoke to experimental research, but by having him in German (after his arrival in

served my apprenticeship with a man Biophysics in 1970), BK ‘warned me who never, under any circumstances, that his German had a strong Anglo- allows the deceptive counsels of Saxon accent’. This was a pun on the human vanity to enter into your fact that BK spoke German with a argument –with a man whose one Saxon accent that ‘was indeed strong, inflexible purpose has always been and in Germany the Sächsische the pursuit and acknowledgement of Akzent of people from Leipzig or truth’. It is very clear that BK learnt Dresden is the source of many jokes’. well from his own hero, because these The time when I recall BK laughing words could serve as well to describe the most was when a young German, © Argent, Godfrey for the 1952 Royal Society, his own values as they described Florian Dreyer, was working in my Hill’s. That, as well as his science, lab. We visited BK in November was why he was an iconic figure for a 1977, to discuss results with 1911 Born, 26 March, Leipzig, Germany 1920 School – König Albert Gymnasium, Leipzig whole generation of post-war tubocurarine. In the Haldane room 1929 First preclinical work, University of Leipzig physiologists and pharmacologists. at UCL, BK said ‘It’s a real pity that 1931 Preclinical exams 1931 Undergraduate work/physiological research with nobody here can understand jokes in Martin Gildemeister Bernard Katz was one of the last of 1933 Siegfried Garten prize Saxon dialect’, but Florian did and 1934 MD degree, University of Leipzig the generation of distinguished they started swapping Saxon jokes in 1935 Short period working at Leipzig Hospital, followed by physiologists who were refugees from arrival at UCL German, accompanied by peals of 1936 First publication with A.V. Hill in Proceedings of the the Third Reich and who contributed laughter. Royal Society 1939/45 Australia, working with John Eccles and Stephen immeasurably to the scientific Kuffler reputation of their adopted country. BK’s father, Max, was a fur 1941 Became a naturalised British citizen 1942/43 Pilot Officer Bernard Katz, Royal Australian Air Force Like many others (Feldberg, Schild, merchant who had left Russia in 1945 Married Marguerite (Rita) Penly Blaschko and Vogt, to name but 1904, and met his wife, Eugenie 1946 Returned to UCL as Assistant Director of Research, Biophysics Research Unit four), BK’s German accent never Rabinowitz, who was of Polish 1950 Appointed Reader in Physiology entirely disappeared. It seemed that origin, in Germany. Until he was six, 1952 Professor of Biophysics and Head of Department, UCL through most of my scientific lifetime Katz was a citizen of Tsarist Russia, Fellow of the Royal Society the most distinguished of my seniors but then, because of the Russian 1957/63 Editor, The Journal of Physiology. Chairman 1961 - 1963 mostly spoke with guttural accents (I Revolution, became stateless, and 1967 Copley Medal of the Royal Society remember my own boss, Heinz remained so until he was 30 when he 1968 Fellow, Royal Society of Physicians 1969 Knighted Schild, a kind and gentle man, became a naturalised British citizen. Foreign Associate, American Academy of Arts and announcing in a strong accent that he Sciences 1970 Awarded Nobel Prize, jointly with Ulf von Euler and had been to a party and was the only In Leipzig, Katz was brought up in Julius Axelrod English person there). It was a what he himself described as a 1976 National Academy of Sciences (USA) 1978 Retired as Head of Biophysics Department, UCL continuous, and salutary, reminder of ‘completely “unorthodox” and liberal 1982 Awarded Orden Pour le mérite für Wissenschaften the follies of the 20th century, and of way’, but nevertheless had his first und Künste 1990 Ralph W. Gerard Prize, Society for Neuroscience the far harder time that these people experience of being an alien Jew in Honorary doctorate, University of Leipzig had than we do now. Science may 1920 when, at the age of nine, he was 1999 Rita Katz died 2000 Unveiling of BronzeTafel at the University of Leipzig have become less gentlemanly, and refused entrance to the Schiller Real- 2003 Died, 20 April funds may be short, but we do not Gymnasium (the head thought that it In science, it is no bad thing to have fear for our lives. would be bad for their reputation to heroes. True, there are some people who resent anyone cleverer than themselves, but personally I like them. I won’t embarrass those of my heroes who are still alive by naming them (especially those who are younger than me), but I can safely say that Bernard Katz was one of them, along with his mentor A.V. Hill.

In the preamble to his inaugural Bernard Katz’s school, the König Albert Gymnasium, Leipzig, in 1912 (left), and today OBITUARIES PN 35 have the entrance exam topped by a stretch and impedance, and although foreigner –a Russian Jew), and he described the work as a ‘prenatal consequently had a classical effort’, it resulted in two papers in education at the König Albert Pflügers Archiv, which secured his Gymnasium. MD degree and also led to his being awarded the Siegfried Garten prize. There he chose to learn Latin and This was in 1933, the year Hitler Greek rather than the more came to power, and Gildemeister was mathematical option (because, he forced to announce publicly that the said, it gave him more time to play prize could not be given to a ‘non- chess in the cafés of Leipzig), though Aryan’ student, though he later gave he acquired a good level of Katz the prize money in private. mathematics anyway. Despite his love of chess, and despite some Martin Gildemeister (1876-1943) At some risk, Katz decided to unpleasant anti-Semitic experiences, complete his medical degree (1934) in he did well at school, and skipped a Leipzig. During 1934 he had read year. In his autobiographical essay A.V. Hill’s Thomas Huxley lecture he relates that one day, in the early (given in Birmingham on 16 1920s, a fellow pupil had, in his November, 1933), and had realised absence ‘called the boys together and that the work he had been doing had informed them of a marvellous plan some slight relation to work being that his father had discussed with done in Hill’s lab at UCL. He had him at home. The plan was that the also read the correspondence between Jewish population of Leipzig should A.V. Hill and Johannes Stark, who be invited to assemble in the had been an eminent physicist, but by underground fair hall, and after this time was no more than a Nazi closing the doors should be killed off scientific Gauleiter. When Stark by filling the hall with poison gas’ . . . tried to defend the Nazi regime ‘This episode has never been erased A.V. Hill, c. 1935 (drawn by Edward Halliday in 1978, against Hill’s criticism of their from my mind, and it gives an from a photograph) dismissal of Jewish scientists, Hill indication of ideas that some people ended the correspondence by noting were harbouring in their heads for 20 certainly evident in BK’s writing (and that gifts of money had been received years before they were able to put the same tendency can be seen in his in response to his appeal for them into practice’. It is hard to disciple, Bert Sakmann, who, on assistance to help colleagues who had appreciate what such an experience being asked to speak to a been driven out of Germany, but he must have been like for a child of 11 distinguished philosophical society, was uncertain whether these or so. told them that he actually preferred donations were the result of his own the motto of the Royal Society, eloquence, or rather should be Katz chose to study medicine, despite Nullius in Verba, to philosophical attributed to Professor Stark’s having no previous experience in the speculation). His preclinical exams, arguments, and he felt sure that some natural sciences, in part as a hedge taken in 1931, were entirely viva voce, thanks were due to Professor Stark against future financial problems. He the anatomy examination being on this account. Katz quotes Hill as started preclinical work at the conducted by Hans Held (of ‘calyx of saying ‘Laughter is the best detergent University of Leipzig in 1929 (the Held’ fame), and the physiology of nonsense’ and goes on to say that classes started at 7 a.m.), where he exam by Martin Gildemeister. these things ‘gave me the first glimpse was taught physics by no less than of A.V. Hill’s personality, and I Peter Debye. He comments ‘I After his preclinical exams, Katz found it so attractive that I made suddenly realised the power and combined his undergraduate work every effort to go and work with him depth of scientific ideas and their with part-time physiological research, as soon as I could’. After working continuous subjection to criticism under the supervision of Martin briefly in a Leipzig Hospital, at the and further trials by experiment. I Gildemeister (1876-1943) who was beginning of February 1935, Bernard felt almost revulsion against my interested in mathematical Katz packed his bags, took a third previous preoccupation with what I approaches to physiological class train ticket to Holland, and now regarded as presumptuous phenomena. Working in the lab also then the Flushing-Harwich ferry. He philosophical speculations and with a had the advantage of keeping him was 23 and had only what he carried, genre of verbose literature that away from the increasingly open anti- a temporary British visa, his League seemed to make a virtue of Semitic views of some of his fellow of Nations stateless-persons pass, a obscurities’. That reaction is students. His work was on muscle letter of recommendation from 36 PN OBITUARIES

(probably not all) central synapses.

Katz remained in Australia from 1939 to 1945, and in 1941 became a naturalised British citizen, so obtaining his first real passport. Soon after, he enlisted with the Royal Australian Air Force, and served as a radar officer on Goodenough Island, New Guinea, in the Pacific war against Japan.1 ‘The commanding officer of 305 Radar Station from October 1942 to March 1943 was Pilot Officer Bernard Katz’ (http://rspas.anu.edu.au/papers/sourc es.html). John Eccles comments, in a letter sent at the time of BK’s Working on squid axon, with Hodgkin, Plymouth Marine Lab, 1948 (Photo by Silvio Weidmann) retirement, that ‘In his nine months on Goodenough Island, behind the Martin Gildemeister and £4 in his Proceedings of the Royal Society (Hill Japanese lines his station was never pocket. et al. 1936). The full text of this, and off the air’. of his many other papers in Royal The next day, Katz climbed the stairs Society journals are available on the Later he met Marguerite Penly, at University College London and JSTOR web site, though sadly his known as Rita, who, incidentally, met A.V. Hill for the first time. Hill major papers in The Journal of was not Jewish. They were married was a remarkable man, not only a Physiology are not yet so easy to straight after the war. A month after great scientist (he had received the obtain. Max Bennett of Sydney the wedding he got a telegram from Nobel prize, with Otto Meyerhof, in University has written a nice A.V. Hill inviting him to return to 1922), but also a statesman who took summary of Katz’s scientific work UCL as Henry Head Fellow of the a large role in helping refugees in the (http://www.ibro.org/secondary/world Royal Society and assistant director pre-war period (see Katz’s news/index.asp?m=v&n=1005). of research in biophysics. Biographical Memoir of Hill, 1978). It is very clear that Hill lived up to Shortly after getting his PhD at Katz returned to UCL in 1946, and Katz’s highest expectations. In his UCL, and a month before the start of autobiographical essay Katz says ‘It the Second World War, he left was an outstanding piece of good Britain for Australia, where he luck to have been taken on as an worked with John Eccles and apprentice to A.V. Hill; it was the Stephen Kuffler. The work of Katz, decisive influence on my life and Kuffler and Eccles in Sydney in 1940 career . . . He was the person from and 1941 was, as Bennett points out, whom I have learned more than ‘the beginning of a new era in anyone else, about science and about synaptic physiology after the one human conduct. . . A.V. Hill was the begun 50 years earlier by Langley most naturally upright man I have and Sherrington’. Use of more ever known. . . To be associated with sophisticated electrical techniques a man of his stature at a formative allowed them to show, using an period of one’s life is indeed a great analysis provided by A. V. Hill, that gift of fortune’. He described these transmitter action is very brief, and first years in Hill’s lab, between 1935 that most of the decay of the and 1939, as ‘the most inspiring endplate potential occurs in the period of my life’. absence of transmitter. This became one of the basic beliefs about fast Katz set to work at UCL on both synaptic transmission for decades to Pilot Officer Bernard Katz on the beach where a nerve and muscle. Within a year his come; it is undoubtedly true at the landing was made to reach Mwananoia (on north shore first paper with Hill appeared in neuromuscular junction and at many of Goodenough Island)

1 Goodenough Island, Allied codename: MICROCOSM, formerly MORATA, one of the D’Entrecasteaux Islands, 20 miles (32 km) across Ward Hunt Strait from the eastern tip of New Guinea, in the Solomon Sea, southwestern Pacific. A part of Papua New Guinea, it lies northwest of Fergusson Island across Moresby Strait. The forested volcanic island, measuring 20 by 15 miles, rises to more than 8,000 feet (2,400 m) in its central mountain range. The island was visited in 1873 by Captain John Moresby, who named it after Commodore James Graham Goodenough. Occupied by Japanese troops for several months in 1942, the island was captured by Allied forces, who built Vivigani airstrip (open to commercial service since 1963). OBITUARIES PN 37 his early work included the discovery noise analysis with Ricardo Miledi in Sakmann, with Erwin Neher, of the phenomenon of inward the early 1970s provided us with the achieved not much later, in 1976, (‘anomalous’) rectification. He also first, albeit indirect, information work that also got a Nobel Prize in started a collaboration with Alan about how single ion channels 1991. Hodgkin that led to the discovery behave, and that allowed many of the that the overshoot of the action remaining gaps in our knowledge of At UCL all the important features of potential results from an influx of synaptic transmission to be filled in. synaptic transmission were sodium ions. Bert Sakmann arrived at UCL as this established, and subsequently many work was going on and relates how of these principles have been found In 1952 Katz succeeded A.V. Hill as there was much discussion about to be true in the brain too. The Professor of Biophysics at UCL, whether recording from a single influence of his work is inestimable, where he headed a department of channel might one day be achieved. not only in physiology, but also in outstanding distinction until 1978. In This of course, is something that pharmacology, in which he laid down the same year he was elected a Fellow some of the most important of the Royal Society fundamental principles. He was justly rewarded by, among many The 1950s and 1960s were a golden other honours, the Nobel Prize in era of important discoveries. With 1970, jointly with Ulf von Euler (of Paul Fatt it was established that Sweden) and Julius Axelrod (of the acetylcholine, acting on receptors at United States), ‘for their discoveries the endplate, opens ‘aqueous pores’ concerning the humoral transmitters in the muscle membrane. This was in the nerve terminals and the one of the roots of the modern idea mechanism for their storage, release of ‘ion channels’, though that term and inactivation’. did not come into common use until later. During the 1950s, spontaneous Katz’s retirement in 1978 certainly miniature synaptic currents were did not mean the end of his influence. observed (with Paul Fatt) and the He continued to referee papers (with essential facts about quantal an astonishing speed – often within a transmitter release were established. day or two), and he took a direct and For pharmacologists, his suggestion lively interest in new developments of a mechanism for partial agonism for many more years. In the 1980s I Portrait done in 1997, by Jenny Hersson-Ringskog (del Castillo & Katz, 1957) was (then an undergraduate student in Physiology- remember him coming, almost seminal. So was the first rigorous Pharmacology). The original hangs in the Starling room running down the stairs, asking to see demonstration, by his PhD student at UCL David Ogden (at that time a post doc Donald Jenkinson, that tubocurarine in my lab), because he’d seen an was a competitive antagonist, in a abstract that David had submitted study that applied to the for a Physiological Society meeting neuromuscular junction the methods and wanted to discuss it. During that devised by BK’s fellow refugee at time, too, I spent two hard weeks UCL, Heinz Schild. working on the mathematics in a paper about sodium channel BK’s perceptiveness in distinguishing inactivation because BK had asked the important from the unimportant about some details, and somehow if was legendary. He realised the small BK asked, it was inconceivable to say and unpromising spontaneous blips that one was busy. I personally owe recorded at the endplate (miniature The Bernard Katz building at UCL him a great debt because his endplate potentials) were not just penetrating questions about the recording artefacts, but a meaning of a 1977 paper that he phenomenon that eventually gave rise read, before it was submitted to to the discovery of quantal Proceedings of the Royal Society, led transmitter release. A similar feat to a whole new field of work for me. came 20 years later when he noticed that the increase in the noisiness of At UCL, Katz is remembered by the the recorded signal when beautiful portrait drawn by an acetylcholine was present was not as undergraduate student, by the boring as it looked, but contained The Orden Pour le mérite für Wissenschaften und creation of the Bernard Katz Chair interesting information. His work on Künste, awarded in 1982 of Biophysics (at present held by 38 PN OBITUARIES

followed by a brief CV which Although Katz spoke little English includes the words ‘1935 Emigration when he first arrived at UCL, his to England, because of repression on writing style was exemplary, and he the grounds of his Jewish origin’. was able and willing to correct the execrable style adopted by some BK did not himself supervise many native speakers of English. His prose PhD students (Paul Fatt, John was simple, straightforward and Nicholls, William Burke, Bob unpretentious, yet very precise, Martin, Donald Jenkinson and something that he attributed to his Stuart Bevan), all of whom went on teachers at the König Albert to do eminent work. But his Gymnasium. He would not use a department became a Mecca for long word when a short one would postdoctoral students from all over do, When it was proposed at the the world. His influence on the 1954 Mill Hill meeting of the training of a large number of the Physiological Society that the terms © University of Leipzig/Carsten Heckmann world’s greatest scientists was huge. ‘sympathetic’ and ‘parasympathetic’ BronzeTafel at the University of Leipzig should be replaced by BK’s seriousness could sometimes ‘orthosympathetic’ and Jonathan Ashmore), and by the make him appear forbidding, and ‘parasympathetic’, his reaction to this naming of a building in his honour. there are many stories about quite unnecessary lengthening was to experiences, sometimes quite suggest ‘sympathetic’ and Bernard Katz’s work has been traumatic, of presenting to him the ‘unsympathetic ‘(Bynum, 1976). His recognised in his birthplace in many first draft of a paper. Equally there writing was totally free of the ways, despite his never having been a are many stories of his jokes and hyperbole that litters so many papers German citizen. He was awarded the light-hearted asides that punctured now, and also free of ‘guest authors’. ‘Orden Pour le mérite für the pomposity of boring committee Those scientific bureaucrats who Wissenschaften und Künste’ (similar meetings. His lack of pomposity is wish to force everyone to work in to the British Order of Merit) in nicely illustrated by an occasion in enormous groups should note that 1982. This prestigious award was 1974 when a young PhD student was his papers rarely have more than two originally a military honour, but its giving his first demonstration at a authors. military function ended in 1918, and Physiological Society meeting. The the civilian version, founded by demonstration involved voltage­ Bernard Katz had an uncanny knack Frederick IV of Prussia in 1842 with clamp of muscle fibres, and his for picking the important part of a the advice of Alexander von supervisor had properly suggested problem, and to leave the rest of us Humboldt, was reinstated in 1922. that when a visitor came in to see the dotting ‘i’s and crossing ‘t’s. Every The charter of the award says ‘The demonstration, he should be asked if new entrant into the field should read number of knights of this peace class he was familiar with the methods his work from beginning to end. is confined to 30 Germans; there may before launching into an explanation. also be 30 foreign knights’ A middle aged man came in and ‘I David Colquhoun (http://www.orden-pourlemerite.de/). went through the motions and asked Department of Pharmacology University College London him if he was familiar with the In 1990 Katz was given an honorary method, to which he replied “..a Acknowledgements doctorate by his alma mater, the little...”. I then explained my The historical facts in this article are largely culled from Bernard University of Leipzig, and in 2000 a demonstration, to which he listened Katz’s autobiographical essay, published in 1998. I have also had generous help from his sons, Jonathan and David, and many of his bronze tablet was unveiled in the patiently’. It was only later that the colleagues and coworkers. University grounds, by the student discovered that his visitor Oberbürgermeister of Leipzig, the had been BK, who had spared the Dean of the Faculty of Medicine and student’s blushes by not revealing his References The History of Neuroscience in Autobiography, Larry R. Squire the chairman of the Albertiner Bund identity. It was the universal (Editor), 607pp, Academic Press 1998 (ISBN: 0126603014). (‘old boys’) of the König Albert experience of his colleagues that he Katz, B. (1978) Archibald Vivian Hill 1886 – 1977. Biographical Gymnasium. The existence of this was a person with enormous Memoirs of Fellows of the Royal Society, 24, 71-149. memorial, and the wording on the enthusiasm, always willing to discuss Bynum, W. F. (1976) A short history of the Physiological Society plaque, was dependent on the efforts with the most junior of them the (1926 – 1976). Journal of Physiology, 263, 23 – 72. of, among others, Frederick Rose details of their work and to offer Secret Action of 305. The Story of RAAF Radar Station No. 305 in (now in Toronto), one of the few advice. There can be few in the field the War with Japan. Norm Smith & Frank Coghlan (1989). An surviving ‘Albertiner’. The of synaptic transmission and ion occasional series (No. 1) published under ‘Heritage Series’ by the Royal Australian Air Force Museum (ISBN 1 86252 594 3), with inscription states (in translation) ‘In channels who have not benefited foreword by B. Katz honour of Sir Bernard Katz’, from his wisdom. OBITUARIES PN 39

electroencephalographer in the Royal in the 1980s, and were still E. Geoffrey Walsh Infirmary of Edinburgh (1951-54), unresolved at his retirement in 1990, 1922 - 2003 then an Honorary Consultant for the but, keeping close links, he enjoyed South East Scotland Regional seeing the Department subsequently Hospital Board (1957-63), later recover and flourish in the next few studying paraplegic patients, and in years. Geoff’s valued contributions to his last years he was Honorary teaching undergraduates, and the fact Neurophysiological Specialist at the that he was continually research Royal Hospital for Sick Children, active for nearly 60 years, as Edinburgh. This last appointment evidenced by his publications, led the recognised his long interest in the University of Edinburgh Medical motor control problems of spastic School exceptionally to repeatedly children, and led to studies on the renew his post-retirement Honorary shaken baby syndrome. Fellowship, which he still held on his death on 26 March, 2003 at the age Meanwhile, his original research and of 80 years. Geoffrey Walsh was born in scholastic contributions, ably Cheltenham on 25 November, 1922. described in Martin Lakie’s tribute, Geoff was particularly pleased to be After education at Cheltenham and including his book The awarded an extra-mural Grammar School (1932-1940) he won physiology of the nervous system Professorship by the University of a Scholarship to Exeter College, (published first in 1957, and in a 2nd Central England in 1998, and the title Oxford University to study medicine. edition in 1964; translated into of his inaugural lecture makes plain He graduated BA with 1st class several languages) led to promotion the multiple facets of his interests in Honours in Animal Physiology in to Senior Lecturer and finally Reader human neurophysiology, including 1943, winning several undergraduate in 1967. His original contributions to his late-developing interest in the fine prizes. human neurophysiology were control of finger movements in recognised by Fellowship of the musicians, alongside his own learning Geoff began his research career in Royal Society of Edinburgh, in 1959, of how to play the flute and the neurophysiology in 1944, still at and his continuing interest in clinical saxophone: ‘Movement control in Oxford, and published a problems by the award of normals, the disabled and musicians: Physiological Society communication Fellowships of the Royal Colleges of muscles, medicine and Mozart’. with David Whitteridge that year. He Physicians of both London (1967) then spent two years as a Rockefeller and Edinburgh (1968). For example, Geoff’s wife, Penny, a charming, student at Harvard University, in 1963-64, while a WHO visiting strong and supportive companion, gaining an MD. Returning to Professor at the Baroda Medical died in 2000, and they are survived Oxford, he graduated MA, BSc and College in India, he advised the by three of their four daughters, and BM BCh in 1947, and pursuing Tuberculosis Chemotherapy Centre grand-children. further clinical training gained the in Madras on testing to identify DTM & H at Liverpool University in vestibular damage from anti­ John A Russell 1948, worked for a while as a ship’s University of Edinburgh tubercular drugs. surgeon, and qualified MRCP (London) in 1950. The next year he All the while Geoff was an active and joined David Whitteridge, who had loyal member of the Physiological Martin Lakie adds: moved to the Chair of Physiology in Society, very frequently giving oral I first met Geoff Walsh 30 years ago. the University of Edinburgh, as a communications, and especially I was then a callow undergraduate Lecturer in the Department of demonstrations at meetings of the student of physiology at Edinburgh. Physiology. Society. He was a member of the At this time I first entered the rather Editorial Board of The Journal of gloomy basement which housed the His research was focused on the Physiology (1965-1972), a member of Human Neurophysiology Lab, and challenges of investigating the Society’s Committee (1983-86), the intriguingly named Special Senses neuromuscular control in humans, and played a key role in the Lab, which were presided over by Dr with a particular interest in the organisation of Society meetings in E.G. Walsh and his technician Mr G. effects of vestibular dysfunction, and Edinburgh. Wright (no first name status in those thus in the neurophysiological basis days). The labs and his office were of balance, and of tremor. His Geoff was bemused and dismayed by very often home to Geoff’s research aims were generally directed the academic leadership problems Dalmatian dog, Tasha. Experimental towards understanding clinical that beset the Edinburgh Medical classes for students were overseen by neurological disorders, and to this School’s Department of Physiology the two gentlemen. For these end he was a part-time 40 PN OBITUARIES teaching sessions, Geoff would often electrical and magnetic stimulation of oblivious to the interest that he was wear his off-white lab coat which the visual cortex (Barlow et al. 1947a, creating. resembled, and might well have been, b). Half a century later Magstim experiments are now much in vogue. Although he was a scholar who loved a nightshirt of the Victorian period. There was an early paper in Nature to read and to write it is perhaps for Centre stage was occupied by a huge with Heinz Wolff (Walsh & Wolff, his experimental work that he will be parallelogram action see-saw by 1951) on the design of a novel beam best remembered. He was an which recumbent subjects could be splitting spectrophotometer. There enthusiastic radio amateur and a very propelled through a distance of a were many papers on various aspects skilled builder of electronic couple of metres towards the ceiling of vestibular sensation in animals and apparatus, often of a high degree of or floor. This apparatus had been man. From this basis, his attention complexity. The seamless transition built in order to test the vestibular had broadened to encompass from valves to transistors to sensitivity to linear acceleration in the standing and balancing mechanisms, integrated circuits and latterly to saggital plane (Walsh, 1964a). These postural stability and instability and computers cannot have been easy to experiments, and others involving in particular, tremor. make. His electronic design ability rotational vestibular stimulation were was remarkable and he built a great naturally popular with students who I subsequently came to know Geoff number of novel circuits to carry out competed to achieve the highest well as I did a PhD under his often complex analogue processes. velocities. Some years earlier there supervision and worked with him as While the design was invariably had been another apparatus that a postdoc for a number of years and excellent, the standard of measured vestibular sensitivity in the we kept in touch thereafter. His construction was often less perfect. transverse direction. To reduce shear industry, intelligence and enthusiasm Experiments would sometimes be forces on the skin the supine subject were formidable and a little punctuated by flashes, bangs and (breathing through a mouthpiece and frightening at first. Fortunately, blue smoke as wires made accidental valve) was entirely immersed in a these characteristics were offset by a contact. On one memorable occasion deep coffin shaped tank of water delightful sense of humour which was a Physiological Society suspended from the ceiling. In without doubt the driest that I have demonstration very nearly came to action, the water would slosh about ever encountered. Although grief when widespread short­ and to minimise this disturbance it possessed of a dry sense of humour circuiting was found to have occurred was rendered more viscous by the there was nothing arid about the man because several of the rubber bands judicious admixture of wallpaper who had the most genuine curiosity holding the circuit boards in place paste and sawdust. The subjects about, and interest in, all aspects of had perished. Such a technical indicated that they had detected the life. He was in the true sense of the malfunction would invariably trigger stimulus by tapping with a hammer word a polymath. He once declared a reaction resembling that of a on the floor of the tank. Their that it was his ambition to parent exasperated by a non­ reaction to the procedure is not understand all scientific subjects to at cooperating child. There would be reported (Walsh, 1961) least first year undergraduate degree an initial astonishment at the level. As well as working hard in his unexpected event, followed by a I remember at the time being spare time to achieve this ambition he period of tutting and mild irritation impressed equally by the ingenious also painted and played the flute. He as repairs were effected. This was nature of the experiments and by the was to some extent an iconoclast who characteristic; although an individual discovery that most of the apparatus cared little for uninformed opinion. of very strongly held beliefs and had been cleverly constructed from a It is hard perhaps to remember a time principles he never publicly expressed combination of vehicle, aircraft and before the ubiquitous Walkman more than a puzzlement and marine scrap. There was, as I later clamped over the ears became a irritation at life’s tribulations. discovered, an even deeper basement commonplace. Many years ago I packed with gleanings from scrap­ watched Geoff waiting in a busy He was interested in travel and yards and surplus stores. Geoff’s public area of the Western General transport. Well known in main early interests had been the Hospital in Edinburgh as we whiled Edinburgh was the steam car that he sensory nervous system and he had away the time before starting an had designed and built although an impressive number of publications experiment. He had over his ears a when I first knew him he generally on this work under his belt, and his large pair of bright red earphones. travelled by motor-bike. There was a erudite, entertaining and eclectic Between the earphones was a spare crash helmet and he would book (Walsh, 1964b) enjoyed a wide centrally mounted radio receiver and sometimes offer the unwary or naïve readership. a short vertical whip antenna a lift on the pillion seat. With a sprouted from his head. The strains group of researchers he measured Working with Horace Barlow he had of Radio 3 were just audible. He head oscillations of volunteer railway published two papers in 1947 on gave every appearance of being passengers in a train consisting of OBITUARIES PN 41 different models of carriage (Walsh, system unstable and resonant. This References Barlow HR, Kohn HI & Walsh EG (1947a). Visual sensations 1966). This train was specially run technique has been recently used to aroused by magnetic fields. Am J Physiol 148(2), 372-375. for the purposes of measurement on study the operation of the CNS Barlow HR, Kohn HI & Walsh EG (1947b). The effect of dark the East Coast line between controller. adaptation and of light upon the electric threshold of the human eye. Edinburgh and Newcastle. (He was Am J Physiol 148(2), 376-381. particularly fond of the account of Finally (Lakie et al. 1984), following Lakie M, Walsh EG & Wright GW (1984). Resonant frequency at the this work that appeared in The Times some pioneering work on the wrist demonstrated by the use of a torque motor: an instrumental analysis of muscle tone in man. J Physiol 353, 265-285. under the neat caption ‘Heads roll on measurement of human muscle tone, the 09.45’). He investigated in he was able to demonstrate that Marshall J & Walsh EG (1956). Physiological tremor. J Neurol Neurosurg Psychiat 19, 260-267. person the motion sickness caused by human muscles behaved the effect of swaying gait of camels. thixotropically, that is they had a Walsh EG, & Wolff HS (1951). Heterochromatic photometry using Nature stiffness which depended not just on rotating filters and a colour wedge. 167, 683. It is perhaps difficult to say what his the size of a movement but also on Walsh EG (1961). Role of the vestibular apparatus in the perception main scientific interest was, but I their history of movement. The of motion on a parallel spring. J Physiol 155, 506-513. would judge that his research always implications that thixotropy has for Walsh EG (1964a). The perception of rhythmically repeated linear centred on recording and the control of movement and the motion in the vertical plane. Q J Exp Physiol 49, 58-65. measurement, usually employing cause of the phenomenon are subjects Walsh EG (1964b). The physiology of the nervous system, 2nd ed. some highly original technique and which are currently receiving Longmans, London. self-constructed apparatus. If Geoff’s widespread attention. Walsh EG (1966). Lateral head sway observed in railway travel. Bio­ research programme was perhaps less med Eng 1, 402-407. focussed and more curiosity-lead Geoff maintained an active interest in Walsh EG (1969). Interference with the tremor of Parkinsonism by than would be generally approved of research beyond retirement. He wrote the application of a rhythmic force. J Physiol 202, 109-110P. nowadays he nevertheless pursued his second book and finished a draft Walsh EG (1970). Tremor at the wrist induced by positive velocity important and complicated problems. of a third. He had a laboratory built feedback. J Physiol 207, 16-17P. Working sometimes on his own, but in his garden and he vigorously more commonly with a small number pursued the study of skilled finger of colleagues, he made and is movements in musicians and others. remembered for fundamental His findings were published on a Special senses teaching in discoveries in four important areas. regular basis right up to the time of his death. The possessor of an Edinburgh First (Marshall & Walsh, 1956), there excellent memory, he was a Andrew Packard reminisces was his suggestion very nearly 50 fascinating source of recondite on some of Geoffrey Walsh’s years ago that physiological tremor information on many aspects of represents in the main filtered noise neurophysiolog to the end of his life. ingenious additions to the which is generated by random motor Physiology Department’s unit activity. To this might be added He was a colourful inhabitant of an basement the subsequent demonstration that it earlier more colourful world. A My last ‘phone call with Geoff Walsh is the resonant properties of the limbs world where the scope of scientific in early March was about a version that imparts a colouration to the investigation was usually limited by of the ‘Asher Box’ (Asher, 1950) (Fig. noise and gives it the appearance of a the apparatus that could be 1) I had built for students at Stanford tuned oscillation. He was dismissive constructed and the skill and University’s Hopkins Marine Station. of ‘tremor generators’. intelligence of the investigator rather This box illustrates the simultaneous than by the size of the research grant contrast illusion and opponent Second (Walsh, 1969), he was one of that could be obtained. A world processing that takes place at the the first to investigate the where intended learning outcomes, level of the retina. entrainment of pathological tremors research assessment exercises, cost using torque motors to ‘drive’ a limb. centres and teaching quality audit did Geoffrey, with his gift for This ingenious approach can, in not exist, yet good research was done resurrecting practical demonstrations principle, distinguish between an and students were taught well. He from the literature, had had a copy of oscillator which is autonomous and once told me that he loved his job the original built by George Wright one which results from a process of because he was paid for doing what for small class teaching in the Special self-re-excitation by a feedback he enjoyed most. That made him an Senses lab at Edinburgh. The mechanism. However, the resulting amateur in the best sense of the apparatus had a bulb in each of four analysis is fraught with difficulties. word. Neurophysiology has lost one chambers, those in the front chamber of its pioneers and the world is a – the ‘surround’ of the visual stimuli Third (Walsh, 1970), he was the first greyer place for his death. – being operated by separate person to employ positive velocity switches. I thought he would feedback (negative damping) in order Martin D. Lakie appreciate my cut-price version made to make the human musculoskeletal University of Birmingham 42 PN OBITUARIES out of a shoe box with only a single, In my experience, Asher’s perception with British Rail. (They external, source of illumination. psychophysical demonstration of the had lent him a train for a week Apart from its ease of construction, simultaneous contrast illusion is more operating out of Waverley station). the subtleties of centre-surround effective than any of the better- On the bed would be a blindfolded phenomena can be better known ones appearing in textbooks student with a second in attendance demonstrated by dispensing with on vision. recording sensations. fixed light sources. Tracing paper in the cut out lid diffuses light from a Over the years, EGW and Hugh When I joined them in 1969, I was lamp at the viewing end and students Begbie had added several ingenious particularly intrigued by the things can see for themselves the effect of pieces of apparatus to the special for vision - Begbie’s speciality. There screening one, and not the other, of senses lab in the Physiology was a large bright (? xenon) lamp the front chambers, while leaving the Department basement. At the bottom with filter in the far blue to see one’s rear ones, providing the ‘centre’, of the stairwell stood a huge swinging pulse and the trails of circulating unchanged. bed – a left-over from the period rouleaux, while fixating a cross in the when EGW had a project on motion middle of the screen. When the blue

The ‘Asher Box’ (Fig. 1), for demonstrating centre/surround properties of visual units, is made of two cardboard shoe boxes, with grey (or white) interiors, one for viewing and the other cannibalised to make internal partitions.

The viewing box is divided longways down the middle by one partition, and crossways by a second three-fifths from the viewing end to make four rectangular chambers. Two circular holes (c. 6 mm diameter) are punched in the cross partition with a leather punch or cork borer about two thirds up from the floor of the box on either side of the middle partition. [Find cork borer sets hidden away in old lab cupboards]. The Figure 1. The Asher Box flat part of the lid of the shoebox is cut out and replaced by tracing paper to act as a diffuser of overhead light. Spectacle-shaped apertures are cut in the end wall of the box for looking into the larger (front) chambers. The viewer sees one hole through into the rear chamber with the left eye, the other hole with the right eye.

In Asher’s original design [as used in Edinburgh], the chambers were illuminated by four lamps: the two rear chambers by a ‘pea-lamp’ from a torch battery, the two front chambers by brighter lamps each with its own switch. In my version, illumination is from an overhead light, the relative positions of lighting and box being so adjusted that left and right sides are lit equally and the front chambers are brighter than the rear ones. The two holes in the cross partition should then appear of equal grey level. In the main experiment, illumination of the two rear chambers remains equal and unchanged.

The version created for teaching in Edinburgh had a stereoscope in the place of the peepholes for the two eyes, and one hole in the cross partition was higher than the other, but I find stereospecs are not necessary.

Uniformity of surfaces in the apparatus is unimportant; contrast is all-important. (A miniaturized photographic greyscale can be placed, for reference, on each of the ‘surrounds’).

Experiment 1 (the main experiment) demonstrates the centre/surround organisation of visual units. The viewer (participant observer) is asked a) to judge the relative grey levels of the two holes in the cross partitions, b) to comment on the effect of reducing the illumination of one of the front chambers with a screen – i.e. darkening the ‘surround’ on that side, c) to say whether his or her judgement changes when it is revealed that the absolute grey levels of the holes have not changed. By arranging that the two halves of the simultaneous contrast illusion were seen separately by the two eyes, Asher was able to argue that the units reponsible are at the level of the retina – a finding subsequently confirmed by neurophysiological experiments on monkeys.

Other experiments include demonstrations of red/green and green/red opponent processing (obtained by replacing the grey, or white, ‘surrounds’ by green and red partitions. OBITUARIES PN 43 screen is viewed through a moving is with the left or the right hand. pinhole, the retinal capillary network Most responses fall short of the supplying the fovea jumps sharply target, and the shortfall is greater in into view – complete with a gap at left visual field than in right – to do the centre corresponding to central with hemispheric separation of the fovea seen dimmer than the rest, two fields, I suspect. As I enter our where rods as well as capillaries are darkened living room, my eye missing. (Of course the same effects movements cause the light of the can be achieved by looking at a blue digital clock on the radio to appear sky on a bright day, but that is more as a bright line interrupted at difficult to arrange in Edinburgh). 50-cycles. When I look to the right, the line is longer, brighter and the Fortunately, some of these regular interruptions more spaced demonstrations survived the cuts and than when I look to the left. I have consequent abandonment of small no reason to believe that this strange class teaching in the Thatcher years. difference is because the velocity of Suitably modified, they could be used my ‘look left’ saccades is less than to advantage in a darkened lecture that of my ‘look right’ ones. So I theatre filled with 200 medical conclude that the perceived difference students where group reactions in the saccades has the same origin as considerably enhance their success. the perceptual ‘contraction’ of left We managed the Pulfrich Pendulum visual field observed in the pointing for binocular stereopsis suspending it experiment. from the pipes in the ceiling above the blackboards. From the back of a Has this directional difference on the lecture theatre the pendulum appears perceived amplitude of one’s to swing out across the heads in the horizontal shifts of gaze been noticed front benches. We even simulated the by others, I wonder? Maurice-Ginsborg effect for perceiving one’s own mini-saccades. Andrew Packard Figure 2. Top, Pupilometer (x1) consists of paired Stazione Zoologica ‘Anton Dohn’, Naples, Italy Instead of an oscilloscope trace, the pinholes pricked through black paper progressively vertically-running spot of light is further apart: accuracy of pinhole diameters and shapes References generated by a rotating slit in front of unimportant. It is held against one eye. Middle, 4 pairs Asher, H. (1950) Contrast in eye and brain. Brit. J. Psychol. 40, 187­ of blur circles seen when contralateral eye is covered. 194 a stationary one mounted on the slide Below, blur circles during consensual reflex, holder of a long-throw projector. The (contralateral eye uncovered). Walsh EG (1964). Physiology of the Nervous System. 2nd ed. London only trouble with these developments was that George was usually still able to see their own blur circles (Fig. perfecting the apparatus when the 2) they could measure (and we could lecture was due to start! Other items do instant statistics on) male and Emiline Lesly Jervis can be kept to an inexpensive female pupil diameters during the 1927-2002 minimum: black-out paper for consensual reflex. pinhole(s) and pieces of red and green acetate supplied to each As always with teaching, it acted as student or shared between two. The an incitement to research. One piece colour filters also doubled up as of apparatus not suitable for the neutral density filters to introduce the large class was a pointing experiment retinal delay (and retinal disparity) – described in Walsh’s book on the required for the Pulfrich Pendulum. Nervous System as a ‘projectionometer.. The large class also had other Author/unpublished’ (Walsh, 1964, advantages. On one occasion, with Fig. 9.19). It tests the accuracy of the Ishihara charts faithfully locating a brief spot of light imaged Emiline Lesly Jervis was recruited to reproduced as slides by Medical at intervals along a scaled board, the Department of Physiology at Photography, we picked up a rare while fixating a central light. Plotting Sheffield University by Professor female tritonope. And the colour the responses of a number of subjects David Smyth as a Research Assistant filters allowed normals to see what it I noticed that accuracy was worse on in 1955 to join his team investigating is like to be red-green colour blind, the left side of the board than on the the mechanisms of intestinal etc. With a class of 200 and everyone right, irrespective of whether pointing transport of hexoses and amino 44 PN OBITUARIES acids. Research on the intestinal eventually recovered. This incident absorption of amino acid contributed to Bill’s decision to enantiomorphs (the title of her thesis) abandon engineering and to study led to her PhD in 1960 two years medicine. after becoming a Lecturer in Physiology. Three papers were With some financial help from his published with David Smyth in The famous father-in-law he went to Journal of Physiology on the topic Edinburgh to study medicine. That between 1959 and 60. She was elected was how Archie came to be born a member of the Physiological there. Bill graduated in medicine in Society in 1960 and became a Senior 1915 and joined the British 80th Field Lecturer in 1974. Lesly, who was Ambulance which saw service first on diabetic, developed diabetic the western front then, until the end retinopathy and began to experience of the war, in Macedonia. Bill impaired vision. She struggled At the end are included some more returned to Edinburgh in 1919 when against the condition and was able to general views held by Archie, in Archie really got to know his father produce enough results for the basis summary form. Archie has read the for the first time. of a paper co-authored with Dr Roy transcripts of our meeting and was in Levin that was published in Nature in essential agreement with what I had In 1920 the family returned to 1966. Unfortunately, it became her written. Launceston, Tasmania where Bill set last major publication as her eyesight up his practice and remained there continued to deteriorate and she Archibald Keverall McIntyre was for the rest of his life. Archie first became sighted in only one eye. It born on 1 May, 1913 in Edinburgh, went to school at the age of eight. made for great difficulty for her Scotland, the second of four children. His mother, a highly cultivated and experimental bench work and when His father, Bill, who was from intellectual person had already taught the sight in this eye also began to Hobart, Tasmania, had studied him his 3Rs and much more. Archie deteriorate she was finally forced to engineering in Sydney and during his attributes his love of poetry to his give up experimental work. Despite time there had met and married mother. Archie’s first years at school her sight disadvantage she devoted Margaret Edgeworth David, were not very happy ones because he herself to teaching physiology to daughter of the Professor of already seemed to know most of dental students and administered Geology. what was being taught. It was not their course for many years. immediately recognised that he was Gradually her condition worsened, Edgeworth David was a distinguished acutely short-sighted and couldn’t see she became practically blind and only scientist and scholar who came to the blackboard from the back of the then did she decide to take early Australia in 1882 as Assistant classroom. Subsequently his parents retirement on health grounds retiring Geological Surveyor for New South decided that Archie should continue from the Department in 1985. She Wales. He became Professor of his education in Sydney and so he died in hospital in Sheffield in 2002 Geology at the University of Sydney spent the last four years of secondary aged 75. in 1891. In 1907, the Nimrod called school at Barker College Hornsby. at Sydney, with Lt Ernest He matriculated in 1929. During this Roy J. Levin Shackleton’s Antarctic expedition. time he got to know better his Reader in Physiology (retd) David accepted an invitation to join famous grandparents as well as his the expedition as geologist, bringing aunt Molly whom he subsequently Archie McIntyre along Douglas Mawson, one of his referred to as his second mother. At Honours’ students. During the age 16, having won a university 1913 – 2002 summer of 1907/08, David led a party exhibition, Archie enrolled for a BSc which climbed the active volcano Mt at Sydney University, studying Archie McIntyre died on the 20 July, Erebus. In 1909, with two others, physics, chemistry, zoology and 2002. The Foundation Professor of Douglas Mawson and an botany. This was Archie’s first Physiology at Monash University, Englishman, Alistair Mackay, David introduction to biology which in Melbourne, Archie can be considered reached the South Magnetic Pole, a those days boys never did at school, to be one of the founders of modern round trip of about 1200 miles: this and he became deeply fascinated by neuroscience in Australia. This piece without food depots and without it. His interest in biology and is based largely on a series of dogs to pull their two sleds. encouragement from his father led conversations I had with Archie Archie to transfer to medicine in his about his life and work. The meeting During the birth of their first child, second year. took place in June 1994. The first Peggy, Madge McIntyre developed part of the account is about his life. puerperal fever from which she Although he found medical school OBITUARIES PN 45 initially difficult, his organised labour. Subsequently he studied the Renshaw. Archie worked with Lloyd approach to learning and his responses of isolated strips of uterine on the tendon jerk. This was one of excellent memory meant he was soon smooth muscle to electrical the foremost laboratories in the at the top of his class. He was one of stimulation and hormones added to world, equipped with the most the select few to be chosen for the bathing solution. modern valve operated electronics. ‘prosector’ in anatomy. Archie’s first introduction to neuroscience came At the outbreak of war Archie was Towards the end of his time in New through one of the lecturers, Kanny, persuaded to join the Air Force. York Archie got a Nuffield who also worked part-time at the Making use of his interest in the Scholarship to work in Cambridge. Kanematsu Institute. After his third vestibular system, he developed a (At about this time his mother was year, when Archie again passed with method of identifying air sickness­ killed in a plane crash on her way high distinctions he was the only prone subjects. These were then back to Tasmania from a meeting of student to do an Honours year, our eliminated from pilot training in the the National Council of Women in equivalent of the Bachelor of Medical USA or Britain. He began to work Brisbane). In Cambridge Archie Science. He worked on blood gas on anti-blackout suits for pilots. He borrowed a bicycle from Alan analysis with Witridge-Davis. It was was assigned as medical officer to Hodgkin to travel to the lab every amusing to hear Archie’s account of Frank Cotton who ran an day. Here he had to build his own how he managed to take blood experimental centrifuge in Sydney. equipment, a muscle stretching device samples from himself ‘using bits of Subsequently Archie was sent to the for frog muscle. During his stay in string and sealing wax’. USA to visit centrifuge labs there and Cambridge he got a lot of help from to Britain where he worked for a time Bryan Matthews, the Head of Archie did his residency at Prince with the Physiological Aviation Department. Alfred Hospital. During these later Medicine Unit run by Bryan years he was befriended by Burkett Matthews, which was based near While in Cambridge Archie received the Professor of Anatomy. He also Farnborough. There the work was on an offer from Jack Eccles to take up had good relations with Harold Dew, ejector seats. Notably, Archie a senior lectureship in Jack’s the Professor of Surgery. In the participated in all of the experiments department in Dunedin, New Department of Surgery Archie began himself, some of which were quite Zealand. This vacancy arose from the working on the sense of balance by dangerous, because he was of the departure of Vic McFarlane to the making recordings from the 8th view that you couldn’t ask others to Chair of Physiology in Queensland. nerve. Here Burkett with his excellent do what you were not prepared to do Eccles was probably particularly library was often able to help. yourself. interested in Archie because he knew Burkett also arranged for Archie to Archie had worked with Lloyd in give some of his first lectures. It was Archie was demobilised in 1946 areas of interest to him. At this time during this time that he began to get having reached the rank of squadron Eccles and Lloyd were locked in a to know better his future wife, Anne. leader and, as he put it, having no debate about the latency of direct They had met earlier, when Archie squadron to lead. At this time he was inhibition, a debate which Eccles was staging a play at his aunt approached by Pansy Wright, eventually won. Molly’s. They became engaged in Professor of Physiology at 1939 and married in 1940. Melbourne University, who offered Archie had first met Eccles while they him a lecturing post. However, were both still in Sydney. Jack was Archie’s interest in the sense of Archie wanted to go overseas to one head of the Kanematsu Institute and balance led him to study eye of the top laboratories to further his Professor of Pathology. At this time movements. He recorded eye postgraduate training. He had briefly Archie also met Bernard Katz and movements with simple surface visited the Rockefeller Institute in Stephen Kuffler both of whom electrodes and a string galvanometer New York at the end of the war and became good friends. During his time and discovered to his astonishment there met Herbert Gasser, the in Cambridge Archie visited Bernard that the eyes moved in the opposite director and Dave Lloyd whose Katz at University College and direction to the head. This led to his interests were in reflexes. Archie was obtained all of the necessary technical first paper in The Journal of awarded a Rockefeller Fellowship details for making microelectrodes. Physiology (McIntyre, 1939). and during the years 1946-1948 He took this information with him to worked at the Institute. The rather Dunedin where with help from Jack His work in obstetrics at the Prince small stipend made life in New York Coombs he built a set-up for Alfred and subsequently at the Royal hard for the family, but somehow recording from spinal neurones with Children’s Hospital left him with a they managed. Other well-known microelectrodes. Initially Eccles was deep interest in the birth process. He neuroscientists working at the not interested but he soon realised began developing methods of Institute at the time were Lorente de the importance of this technique. He recording uterine contractions during No, a student of Cajal and Birdsey began using Archie’s equipment for 46 PN OBITUARIES experiments that would ultimately organs supplied by the peripheral for Physiological Sciences. Archie bring him the Nobel Prize. Archie nerves which he, Gasser, had studied. retired in 1978. In 1981-1983 he was was obliged to go and work on This comment eventually led to the the inaugural President of the something else. three landmark papers on sensory Australian Physiological and receptors by Hunt and McIntyre Pharmacological Society (APPS). During the early years in Dunedin (1960a, 1960b, 1960c). Eccles and McIntyre briefly worked Archie and Anne retired to together. This was work on During 1959-1960 Archie took study Launceston, Tasmania, where Archie chromatolysis in motoneurones and leave, six months at University had a brother and sister as well as on disuse. Archie did most of the College, London, then a second six nieces and nephews. Anne designed dissections because he was so much months in Salt Lake City, Utah. In and supervised the construction of better at it, having been trained by Utah, Archie and Cuy carried out the their home, Montacute, perched on Lloyd. In writing up the experiments experiments that led to those three the crest of a ridge, overlooking the it seemed that Eccles always wanted papers. There he also met Ed Perl Tamar Valley on the outskirts of to speculate further than the evidence and Carlos Eyzaguirre. Launceston. At this time Archie allowed and often the speculation became interested in wine making. was declared as a firm conclusion. Late in 1961 Archie was invited to Here his thorough training in apply for the Chair at Monash chemistry came to the fore. About 50 In 1951 Eccles took up the chair at University, and after some hesitation vines were planted and soon Archie the ANU in Canberra and Archie he accepted. His recollection of the and Anne were self-sufficient in wine became Acting Head in Dunedin, early days at Monash were that supplies. I remember, from time to then Head in 1952. Archie remained everything seemed to change so time, sending Archie various pieces of at this post for the next nine years, rapidly. He would plan buildings for glassware and other laboratory items perhaps some of the happiest years of a set number of students, then that to help equip his blossoming his career. Many students passed number would be doubled. Archie oenological analysis laboratory. Even through Archie’s department some of was concerned that he had to set up a today empty bottles of various whom later became well-known in whole department from scratch. He Montacute vintages adorn the shelves their own right, people like W.I. put much importance on the selection of my laboratory. McDonald, Peter Gage, Julian Jack, of staff and soon it was a vigorous, Richard Mark, Ainsley Iggo, John thriving department, establishing its In retirement Archie remained in Ludbrook, John Hubbard and reputation locally and overseas. touch with some of the areas of his Austin Doyle. Archie attracted a Archie believed that the best interests, which included comparative zoologist, Geoff Satchell, to the approach to the teaching of neuroscience. In the period 1982-1990 department and John Veale who had neuroscience was an integrated one. Archie came out of retirement at double degrees in Physics and However, many of his early attempts regular intervals to carry out Medicine joined him from Auckland. in this direction were frustrated by experiments with myself and friends. Many years later, it was Geoff the lack of cooperation from other With John Rawson we showed for Satchell who introduced me to departments. the first time that tendon organ Archie. afferents projected to the cerebral In 1963 Archie was elected to the cortex. In a memorable series of In 1953 Archie gave a paper in Australian Academy of Science. He experiments in which Ainsley Iggo Montreal on the disuse work with became a Member of Council of the and Ed Gregory participated, we Eccles and he used that occasion to Academy from 1968-1974 and in began to explore the electric sense in spend a couple of months back in 1970 was elected Secretary, Biological the platypus. These experiments often Dave Lloyd’s lab. Lloyd was working Sciences. During this time he was went on all night. I remember the with Cuy Hunt at this time. Hunt involved in many activities relating to recording sessions would be and McIntyre became close friends. Physiology and Neuroscience. He interrupted, from time to time, by Archie was also deeply impressed by was President of the Australian and deep philosophical discussions and Herbert Gasser, the director of the New Zealand Association for the there were occasions when Archie Rockefeller. Apparently Gasser used Advancement of Science (ANZAAS), would burst forth with a stanza of to wander into the laboratory rather on Australian Research Grants one of his favourite poems. We all casually and in the ensuing Committee (ARGC) and National got a lot of pleasure out of these conversation was known to often Health and Medical Research collaborative efforts and for me it make, in passing, rather pertinent Council of Australia committees, a was a time when my friendship with remarks about some problem or member of the Programme Archie grew ever closer. other. So it was with Archie - Gasser Committee of International Union of mentioned that little was known of Physiological Sciences (IUPS) and During the subsequent years Archie’s the properties of the cutaneous sense Chairman of the National Committee health deteriorated and he and Anne OBITUARIES PN 47 eventually found it necessary to leave something different. It is also what isn’t? Research should also be Montacute to come and live in a important in the lectures to give the part of someone’s intellectual retirement village close to the centre students a historical perspective of training, to try to find out something of Launceston. After a brief illness, the subject. In doing so it will remind new, if they can. Here the intellectual Archie died in hospital on the them of the continually evolving achievement should be rewarded, not morning of Saturday 20 July, 2002. nature of knowledge and hopefully the practical outcome. Research and He was 89 years old. instil in them a sense of humility, an research-related activities seem to be awareness that the present state of good for the morale of a university Uwe Proske knowledge is only one step along a department. Another trend in recent Department of Physiology never-ending road. In presenting this years is to tailor research Monash University, Melbourne, Australia kind of view it is especially helpful to programmes to the duration of the draw from personal experience, how period of external funding. The risk Acknowledgements one’s own contribution came about is that people will tend to pursue the I would like to thank members of Archie’s family, particularly his wife Anne, for talking with me about Archie’s life and work. I also thank and how it was incorporated into the funds rather than the knowledge. Archie’s sister, Anne, for her comments on the manuscript and for body of knowledge. For most of his providing some of the historical details. life, Archie was interested in the The future of neuroscience workings of the brain. Despite much There is obviously an enormous References progress, so very little is known contribution now being made by Hunt CC & McIntyre AK (1960a) Characteristics of response from about it, even today. It is in this kind molecular biology. But remember, receptors from the flexor longus digitorum muscle and the adjoining interosseous region of the cat. J Physiol 153, 74-87. of situation where a scientists’ sense many people came into molecular of humility is important. biology trained as biochemists, Hunt CC & McIntyre AK (1960b) Properties of cutaneous touch receptors in cat. microbiologists or immunologists. J Physiol 153, 88-98. Looking back on his career, There is therefore the risk of losing what are some of his fondest the broader view. It is important to Hunt CC & McIntyre AK (1960c) An analysis of fibre diameter and memories? receptor characteristics of myelinated cutaneous afferent fibres in consider the organism as a whole and cat. J Physiol 153, 99-112. First and foremost there are the to try to understand integrative McIntyre AK (1939) The quick component of nystagmus. J Physiol students. He learned so much from aspects. For that it is necessary to 97, 8-16. them. And at all levels. Sometimes at have a good general knowledge of (This obituary was first published in Clinical and Experimental the end of a lecture an undergraduate biology. Concerning our Pharmacology and Physiology (2003) 30, 303-306.) student would ask what at first sight understanding of the brain, obviously seemed a silly question. On reflection, some of the recent work, at the Some of Archie’s personal it often turned out that the answer cellular level, on isolated brain tissue views was not at all obvious. There were has had a major impact. Again it will even occasions where it could lead to be important to assemble the various Concerning the research a new line of inquiry in research. parts into a meaningful whole. activities by members of Most of Archie’s students have kept Perhaps computers will be able to staff of a department in touch over the years and it was a help, as well as modern imaging Archie believed that while not constant source of pleasure to him to techniques. Finally, construction of everyone has a natural aptitude for see them succeed in their work. models of how the brain works are research, everyone should be well and good. But they must be encouraged to do something. Those Pure versus applied research firmly based on experimental who are unable to initiate projects by The discussions over this question observations and they are only as themselves should be encouraged to seem to have heated up in recent good as the questions they raise, join other existing active groups. If years. In the early days, whether questions that can be tested by someone only teaches, and teaches something had a useful, practical experiment. An all-embracing model the same thing year after year, they outcome was a consideration, but not that purports to explain everything, become stale and their views out-of­ a major one. If research is not driven stifles enquiry and leaves us with a date as the field moves on. It is by the pressures of a useful outcome, false sense of assurance about our important to be personally involved the work often seems to be more understanding of the world around in some aspect of the work which one objective. And who is to say what us. teaches, to be doing something new, knowledge is going to be useful, and

Inaugural Lecture

Regarding the sad death of Sir Bernard Katz, I was browsing among some old papers in a second-hand book store in Glasgow a few years back and came across a print of Sir Bernard’s Inaugural Lecture (Different Forms of Signalling employed by the Nervous System. An Inaugural Lecture delivered at University College London on 31 January, 1952. Published by H.K. Lewis & Co Ltd). I enjoyed reading this enormously and thought it might be of more emotional value to any of our Members who perhaps actually aattended the Lecture and had no record of it. I have therefore passed it to the Publications Office and it will be made available on the Society’s web site (www.physoc.org) Chris Hillier Glasgow Caledonian University 48 PN OBITUARIES

1979 he left academia and began the notably evening primrose oil, as David Horrobin second major phase of his career potential remedies for many 1939 – 2003 when he set up the Efamol Research conditions, and funded both basic Institute in Nova Scotia, which and clinical research into their spawned the biotechnology company actions. Only a few of these potential Scotia Pharmaceuticals in 1987. uses have resulted in accepted David ran Scotia until leaving the treatments, which has led some company after a boardroom struggle commentators to view David’s work in 1997 to form Laxdale Ltd, which at Scotia with a slightly jaundiced eye he ran until his death. – somewhat harshly, I feel, given the enormous difficulties in bringing new I got to know David well in the 70s medicines to fruition. Although during three years he spent in the Scotia is no longer trading, a search Newcastle Physiology Department on Medline reveals that research into and subsequently when he persuaded gamma-linolenic acid continues – me to found and edit the journal Cell with nearly 100 papers published in Calcium. Characteristics of his that each of the last three years – and the most stick in my mind are his importance of PUFAs in physiology intelligence, his unflagging and medicine cannot be disputed. As enthusiasm for new ideas and his David Horrobin, who died of a tireless promoter of research into generosity. David was always trying lymphoma on 1 April was a ‘full­ PUFAs, David Horrobin deserves to to do something new, and was never time’ physiologist for only the early take some of the credit for this. content to stand still. He was also an part of his career. Because of this, I excellent teacher and inspirer of Numerous obituaries of David suspect his name may be less well­ others, always ready to spend time Horrobin appeared in the national known to Society members than to with people to get the point across. and specialist press. Several are worth people in medicine or the reading, notably those in the Times, pharmaceutical business. However, David was also, needless to say, The Scotsman, and The Lancet, but he remained an active member of the prolific. When he came to work in the one that has attracted the most Society throughout his working life, a Newcastle he was already the author attention was a bizarre, negative, and testament to his lifelong search for of a classic textbook for medical deeply ill-judged one which appeared new ideas, particularly in the area of students, written during his time in in the British Medical Journal, and research into polyunsaturated fatty Nairobi, and of several other books which caused considerable hurt to acids, and latterly into schizophrenia. besides, including a noted guidebook David’s family. What the author of to East Africa! He published a huge David was a true ‘renaissance man’. this hatchet-job had against David is number of articles and several more He was, inter alia, scientist – and one hard to fathom, but she unwittingly books, culminating in his recent book who experimented on himself at that ended up providing him with a rather The Madness of Adam and Eve: Did - teacher, author, journal founder special memorial. Within days of the Schizophrenia Shape Humanity? and editor, publisher, research obituary appearing, over 100 people (Bantam Press, 2001), which was charity president, entrepreneur and – friends, family, former colleagues short-listed for the Aventis Science CEO. More than enough for several and other researchers, or just plain Book Prize the following year. lifetimes - and I have probably interested readers – had written in to omitted several other roles. He was the BMJ to reject her verdict on Throughout his career David was also someone who spoke his mind – David and, in many cases, share their always ready to argue his ideas in frequently and eloquently – and reminiscences of this exceptional print, whether scientific or in what rather enjoyed a good argument. person. This response exceeded in one might call the ‘politics’ of volume the correspondence produced refereeing and funding. This The bare facts of David’s career are by any other piece the BMJ has ever outspokenness meant that some in remarkable enough. He won a printed. The letters, which can be the scientific and medical scholarship to Oxford to read read on the BMJ website, make establishment viewed him as an Medicine and, following clinical and fascinating reading, and give a real irritant. But it is David’s later career research training in London, became sense of the man, his life and work, as a pharmaceutical scientist­ Professor of Medical Physiology in and above all his gift for inspiring entrepreneur that generated the most Nairobi at the age of 31. From there others. controversy, both in his lifetime and he moved to Newcastle as Reader in beyond it. Scotia promoted Maynard Case Physiology in 1972, and to Montreal polyunsaturated fatty acids (PUFAs) School of Biological Sciences as Professor of Medicine in 1975. In and products containing them, University of Manchester BOOK REVIEWS PN 49

contributions about colonic and renal may be less sensitive to PPIs and Mechanisms and family members, which comprise other drugs, and it would have been different heterodimers. This section interesting to see a pharmacogenomic Consequences of Proton also includes curiously placed contribution in the structure:function chapters on duodenal bicarbonate section. However, it seems to me that Transport secretion and the effects of ethanol the real future of this field lies more Tetsuro Urushidani, John G. on gastric cell volume and gap in the consequences of inhibition of Forte, George Sachs junctions. Further sections include a proton pumps, either by drugs or by Kluwer Academic Publishers, strong set of contributions on H. pylori- induced parietal cell transgenic mouse models and atrophy, and the trophic effects of US$112, 372 pp. proliferation, insights into parietal the secondary hypergastrinaemia ISBN 1-4020-7059-4 cell signal transduction, and studies which results. This will require less Appropriately, I washed down my of the parietal cell cytokeleton and reductionist models for study, and ranitidine with a strong black coffee membrane trafficking, important more joined-up physiology, such as to set me up to read this book. This given the profound structural that facilitated by the gastrin volume is a typical synthesis of changes that occur in a stimulated transgenic models presented herein. conference proceedings, with the parietal cell and accompanied by inevitable diverse range in quality of some impressive scanning EM One final point; it was good to know contributions that this brings. Pasting imagery. the book was printed on Acid Free presentation blots, real time imaging, Paper. immunohistochemistry, etc. directly However, the second part of the title, into the authors texts results in an the promised ‘consequences of proton John McLaughlin University of Manchester unfortunate number of barely clear transport’ failed to really materialise or totally uninterpretable figures, much, and this is where the interest with some outstandingly small really lies in practical (all right, Review of Exercise reduced fonts (a few just visible if clinical – I have to admit here to held very close in a good light). being a practising clinician) terms. Physiology: People and Nevertheless, the book provides an The presented work fails to convince excellent snapshot of where gastric that, for other than the reductionist Ideas proton pump physiology, purist, the proton pump is deserving Edited by Charles M Tipton predominantly molecular and of such ongoing attention. PPIs are Published for the American arguably the most clinically effective cellular, is, or at least was in August Physiological Society by 2001. The Pharma sponsorship of drugs in any current usage, and it is this meeting by several leading difficult to see that other upstream Oxford University Press, New Proton Pump Inhibitor (PPI) parietal cell signalling pathways York, £69.50 (hardback), manufacturers is noted. could ever become more attractive 510pp. ISBN-19-512527-4 therapeutic targets than the final Unfortunately, this book delivers common pathway, i.e. the proton only in part on its title: ‘mechanisms’ pump itself. This volume is part of the People and are covered in fine detail, with a Ideas series of the American particularly sturdy first section on Clinically, diseases of gastric acid Physiological Society. As Charles structure and function of H+,K+- secretion are almost always soluble Tipton, the Editor, makes clear, the ATPase, and with welcome by current therapy. A few patients acknowledgement of the existence of Other books received

Those marked with an asterisk (*) are still available for review. Any reader wishing to receive the book and write a short review should contact [email protected]

* Proteinase and Peptidase Inhibition. Recent potential targets for drug development. Edited by H. John Smith and Claire Simons. Taylor & Francis, 412 pp. ISBN 0-415-27349-8

Signalers and Receivers. Mechanisms and evolution of arthropod communication. Michael D. Greenfield. Oxford University Press, 414 pp. ISBN 0-19-513452-4

An Holistic Guide to Anatomy & Physiology. Tina Parsons. Thomson Publishing Services, £15.99, 282 pp. ISBN 1-86152-976-7 50 PN BOOK REVIEWS exercise physiology as a sub­ Needham’s wonderful book, now 30­ discipline of physiology in the odd years old (Needham, 1971). Diseases of the lymphatics American Physiological Society is a However, as she says in the N Browse, KG Burnand & PS relatively recent development, introduction to Machina Carnis, she Mortimer. London: Arnold, although studies of the physiology of spent years writing it. None of the exercise per se in the modern sense authors of this one have had that 2003. 336 pp, £145.00. are roughly 100 years old. luxury. Given the constraints on ISBN 0 340 76203 9 their time, they have done a rather In his introduction Charlie Tipton good job although I think it is a great All physiologists know about the mentions the fact that exercise elicits pity that the Editor did not persuade importance of the lymphatics, at least integrated physiological responses Dirk Pette or Gerta Vrboba to write in a rather theoretical sort of way. but the contributions almost on the mutability of muscle fibre But even 106 years after Starling laid completely ignore this aspect and types, and the whole question of the foundation for our modern deal with the development of current protein metabolism in exercise, in understanding of lymph formation, ideas concerning the operation of which I am particularly interested, the lymphatics remain substantially a various systems of the body during gets no mention whatsoever (though hidden system, perhaps not least exercise. The contributors, many of a couple of my own earlier papers are because it’s the red stuff that grabs whom I know personally, are cited, I’m pleased to find). certainly what would now be our attention if we hurt ourselves or regarded as elder statesmen of the There are some sloppy and some if it stops going round. Everyone field (with the sad exception of Carl hilarious aspects to the book. My knows who inferred the circulation of Gisolfi who died after submitting his old mentor, Richard Edwards, is the blood and many could probably chapter). This places them in a good mentioned in the index but only one dredge up the name of the chap who position to review the historical of the pages cited deals with him, the proved the circuit by describing developments in their area, especially other dealing with some other capillaries. But I doubt if even a since almost all of these Edwards. And, astonishingly, despite handful of readers could name the developments have occurred in the one of the scientists pictured in a people who first described the lacteals last 30 years - and the total literature snapshot of Whipp and Wasserman and peripheral lymphatics, or who does not extend much beyond 30 being a co-author of the chapter in first correctly suggested what years earlier than that. which the photograph appears, the lymphatics are for (I was certainly legend has their positions in the guilty as charged). In reviewing this book I found myself photograph transposed! Very This exceptionally well-illustrated asking a number of questions. Freudian! Would I use the book in preparing book is an excellent antidote to lectures or giving seminars to senior So, all in all a book to dip into, one lymphatic vagueness. It is divided and postgraduate students? Did the from which to pilfer anecdotes to into two parts, the first dealing with book give me insights into areas of introduce lectures and certainly one general principles and the second physiology beyond that in which I from which to extract many examples with the management of clinical work? Was I engrossed in the stories of the foolish persistence of brilliant problems. In the first part there are told? Were photographs of the scientists in following patently wrong highly informative historical and participants and their laboratories directions (e.g. the venerable A V anatomical overviews, as well as a illuminating? Most of my responses Hill’s insistence that lactate was the good description of the formation are positive and although sometimes cause and not the result of muscular and propulsion of lymph. The some of the participants are a little contraction). Anything which helps surgical pathology of the lymphatics self-serving in describing their own persuade young physiologists that is well-described, though as a achievements within the history of scientific life did not begin 10 years pathologist and erstwhile physiologist the subject, there were no egregious ago is a good thing. I was disappointed that the errors that I could spot. I was a little pathophysiology of the lymphatics – disappointed that there was so little Michael J. Rennie for example their role in on biophysics of muscle contraction, University of Dundee immunosurveillance, lymphocyte especially since the classic circulation and particulate matter monograph of Woledge, Curtin and transport – was hardly covered. Homsher is now 18 years old References Other chapters deal with Dorothy M Needham (1971). Machina Carnis: Biochemistry of development of the lymphatics, the (Woledge et al, 1985). None of the Muscular Contraction and its Historical Development. Cambridge contributions gave me as much University Press, Cambridge 1971. ISBN 0-52-107974-8. classification and diagnosis of lymphoedema and the general intellectual pleasure as reading the Roger A Woledge, Nancy A Curtin, Earl Homsha (1985). Energetic aspect of muscle contraction. Monograph of the Physiological principles of medical and surgical same subjects covered at about the Society No 41. Academic Press. ISBN 0-12-761580-6. same degree of detail in Dorothy treatment. BOOK REVIEWS PN 51

I’m sure that these latter chapters, as antacids, diet or bedrest failed (as it well as the whole of the second part Peptic ulcer: rise and fall often did), there was a whole variety of the book, will be a real eye-opener Wellcome witnesses to of surgical options, some more heroic for many physiologists, putting flesh than others and none of which were twentieth century medicine, (as it were) on their theoretical entirely satisfactory. Then, suddenly, understanding of the lymphatics. It’s volume 14. Edited by DA a whole medical and surgical era quite easy to write the Starling Christie & EM Tansey. The came to an end with the introduction equation on a blackboard and Wellcome Trust, 2002. 143 of H2 receptor antagonists in the declaim its importance to dazed pp, £10.00 plus postage. 1970s. And then, just as everyone was groups of students for many years getting used to the fact that there was without ever really appreciating how ISBN 0 85484 084 2 now an established treatment for anatomically devastating the effects The series of Wellcome witness peptic ulcer, albeit one that required of lymphatic dysfunction can be. You seminars have been organised to continuing medication, there was will be in no doubt after a look illuminate recent medical history by another dramatic twist. In the early through this text. bringing together people who were 1980s peptic ulcer turned out to be an involved with a particular issue so infectious disease. The causative Another point which came over that they can ‘discuss, debate, agree organism, Helicobacter pylori, is a strongly to me (and which may be or disagree about their memories’. bacterium with an unusual salutary for those who feel that ever The results, one of which is environmental niche and a more detailed basic science is the key represented by this volume, are not predilection for damaging the to solving humanity’s ills) is that textbooks, but nevertheless make stomach’s self-defense mechanism, there are often times in human fascinating reading for anyone with a causing it to locally dissolve itself. disease when even a highly detailed bit of background knowledge on the Pathologists had been seeing the bug understanding of the cause of a subject under discussion. in histological sections for years, but problem is of hardly any help in ignoring it as ‘contamination’ - a framing a solution to it. If you have Peptic ulcer is almost shocking for good example of seeing but not established lymphoedema for the succession of aetiological theories understanding. example (and over 120 million people and associated treatments which have do), there is little help to be had from come and gone in a relatively short Those of you looking for a Nobel modern physiology – genomic, time. The disease itself seems to have prize take note, there are other proteomic or otherwise. On the other come and gone as well, apparently common diseases which currently hand, a sound surgical approach, being relatively rare before the have complicated causative theories, thorough anatomical knowledge and twentieth century, reaching a peak but which may also turn out to be at some straightforward, old-fashioned around about 1950 when it affected least partly infectious in origin. Pre­ applied physiology can help quite a perhaps 10% of men, and eminent among these is arterial lot. subsequently declining again for atheroma - the main cause of heart reasons which are not entirely clear. attacks and strokes. In thirty or fifty The editors of this book – two Haemorrhage and perforation were years time, Volume n of the witness professors of surgery and a professor common complications, not series may be devoted to that story. of medicine, each of whom has made infrequently fatal. Even within the But in the meantime, the ebb and substantial contributions to the field last 30 years ‘stress’ was thought to flow of the story of peptic ulcer, told – are to be congratulated on be an important causative factor. by those who lived it, is an absorbing producing a readable, well­ Gastric acid production was also testament to the winding and often referenced, wide-ranging and important, since patients with unpredictable path of medical authoritative text which will be atrophic gastritis and little acid science. valued by a diverse readership. secretion did not develop ulcers. When ‘medical’ treatment with John A Lee John A Lee

Royal Society elections John Robson has recently been appointed a Fellow of the Royal Society, and Denis Baylor a Foreign Member.

Member’s success Dr Stephen Gomez, Principal Lecturer in Human Physiology at the University of the West of England, has won a prestigious national teaching fellowship prize of £50,000, awarded by the National Teaching Fellowship Scheme, which was set up in 2000 to reward excellence in teaching and learning. Stephen has a track record of innovative physiology teaching and has introduced credit-rating of placement learning. 52 PN NOTICEBOARD

FORTHCOMING PHYSIOLOGICAL MOLECULAR TECHNIQUES FOR LIFE INTERNATIONAL WORKSHOP IN SOCIETY MEETINGS SCIENCES NEUROSCIENCE 20 – 22 August, 2003 Bucharest, Romania 23 – 25 September, 2003 2003 PCR Theory and Practice Manchester 9 – 12 September A three day workshop to familiarise participants with this essential Ischemia/Hypoxia in the Brain Cambridge 17 – 19 December technique. Organised by the Physiological Society and the National Price: £425 Neurosciences Society of Romania Online registration: http://www.snn.ro/workshop2003 2004 8 – 12 September, 2003 Glasgow 29 – 31 March 26 – 30 January, 2004 Babraham Institute, Cambridge – 1 May Cardiff 6 – 7 July Manipulating Nucleic Acids FIRST INTERNATIONAL CONFERENCE OF Cork 1 – 3 September A five day practical workshop to introduce participants to techniques King’s College London 16 – 18 December used in molecular biology investigations and to facilitate THE NATIONAL NEUROSCIENCES development of core molecular biology skills SOCIETY OF ROMANIA Price: £715 University of Medicine and Pharmacy, Bucharest, Romania 2005 26 – 27 September, 2003 Bristol 20 – 22 July Further details from: Registration: www.snn.ro Mrs J Pierotti IUPS 2005 – 35th CONGRESS OF THE MTLS Administrator INTERNATIONAL UNION OF Biological and Biomedical Sciences Glasgow Caledonian University PHYSIOLOGICAL SCIENCES Cowcaddens Road BIOSCIENCE 2004 - FROM MOLECULES San Diego, CA, USA Glasgow G4 0BA TO ORGANISMS 31 March – 5 April, 2005 Scotland SECC, Glasgow, UK UK 18 - 22 July 2004 IUPS 2005 is being organised by the six member societies of the US Tel: 0141 331 3209 National Committee of the IUPS, the American Physiological Society, Fax: 0141 331 3208 Poster abstract deadline: 23 April 2004 the Society for Neuroscience, the Microcirculatory Society, the Email: [email protected] Early registration deadline: 18 May 2004 Society of General Physiologists, the Biomedical Engineering Society www.BioScience2004.org and the Society for Integrative and Comparative Biology, under the Website: www.caledonian.ac.uk/mtls auspices of the US National Academy of Sciences. http://www.IUPS2005.org Noticeboard THE CONGRESS OF THE LATIN- Notices for the Winter 2003 edition of Physiology News THE BIOLOGY OF CHLORIDE AMERICAN ASSOCIATION OF should reach the Publications Office Woods Hole, USA PHYSIOLOGICAL SOCIETIES (ALACF) ([email protected]) by 2 September, 2003. 3 – 7 September, 2003 AND THE BRAZILIAN PHYSIOLOGICAL Please note that whilst members are welcome to advertise 57th annual meeting and symposium of the Society of General SOCIETY (SBFIS) relevant events in Physiology News and on the Society’s Physiologists. Ribeirao Preto, State of Sao Paulo, Brazil website, advertisements via email will be restricted to Further details from: http://www.emory.edu/CELLBIO/SGP/sgp.htm 1 – 4 September, 2003 events sponsored by the Physiological Society. Clockwise from top: Radar station 305 at Mwananoia (Goodenough Island, New Guinea), where Bernard Katz served as the first commanding office from October 1942 to March 1943. Pilot officer Bernard Katz on the beach where a landing was made to reach Mwananoia. Portrait of Bernard Katz by Jenny Hersson-Ringskog (1997). Work at Plymouth Marine Laboratory in 1948 with Alan Hodgkin led to the descovery that the overshoot of the action potential results from an influx of sodium ions. Recordings of miniature (top) and evoked (lower) end-plate potentials (Fatt & Katz 1950, Nature 166, 597). Maps showing the location of the radar station.