RA5a: Structure,environment and staffing policy
Our research interests include many areas of pharmacology. We have particular strengths in cell signalling; ion channels; receptors and endocytosis; cardiovascular and autonomic pharmacology; neuropharmacology; and chemotherapy. This breadth is enhanced further by the many collaborations staff enjoy with other groups, including many from other disciplines: clinicians (Ferguson, Taylor, Barrand, Hiley, Fan), vets (Callingham), engineers (Hladky, Henderson), chemists (Waring, Taylor), computer scientists (Thorn) and the pharmaceutical industry (McNaughton, Richardson, Fan). There are strong links between labs in each research area, but the Department is well-integrated with no boundaries between research areas. Among many other advantages, this allows us to provide undergraduate teaching in diverse areas of pharmacology and neuroscience and to provide graduate students and postdoctoral staff with broad training programmes. The grouping of staff in this document is simply for ease of presentation.
We aim to advance fundamental research of the highest quality while maintaining excellence in teaching. Indeed we believe there to be a synergistic relationship between high-quality teaching (24 in our recent QAA assessment) and excellence in research. We aim to foster the careers of promising young researchers by funding positions (PhD students, Pharmacology Fellows), by providing a supportive research environment (research infrastructure, start-up funds), and by effective provision of training for independent research careers (mentors for PhD students and younger academic staff, Graduate School, University Staff Development Programme).
Our achievement of these aims has been assisted by our partnership with Glaxo Wellcome (now GSK). The Glaxo Institute for Applied Pharmacology (GIAP, Head Professor P.P.A. Humphrey) has been embedded in the Department since 1992 and interactions with its staff have led to a number of joint research projects. Funds provided by this partnership (the Glaxo Fund) have enabled us to improve the infrastructure of the Department (through refurbishment, core equipment, Computer Officer, animal house technician), and to fund several PhD studentships (17 full and 7 partial studentships during the review period), five independent Pharmacology Fellowships, and a Departmental lecturer (Barrand). After 9 successful years in the Department, GIAP will close in 2002 following the merger of Glaxo Wellcome with SmithKline Beecham. Our plans to develop new initiatives in the vacated space are described below.
The entire Department and GIAP are housed in a single purpose-built building (completed in 1988) in close proximity to other life sciences departments and libraries. An extension was added in 1996, and refurbishment of core facilities, labs, animal house and a computer suite for research students have all been completed since then.
Staff, Research Planning and Management
There are 29 category A staff: 19 are academic staff (3 Professors, of whom Irvine is a Royal Society Research Professor; 3 Readers; and 13 lecturers). A newly appointed lecturer (Genazzani) was recently awarded a BBSRC Sir David Phillips Fellowship, allowing the appointment of Van Veen to a 5-year temporary lectureship. Hinchliffe is an MRC Career Development Fellow. Ford, Koenig and Thomas hold Pharmacology Fellowships (funded by the Department). Four staff are stipendiary College Research Fellows (Berge, Gergely, Smith, and White), and Sellers is a University-employed member of GIAP. In addition there are three senior staff in GIAP employed by GlaxoSmithKline (Humphrey, Feniuk, Michel). Barnard has a grant from the Wellcome Trust.
All academic staff are appraised every 2 years, others annually. A senior member of staff serves as mentor for each of the Pharmacology Fellows. Staff are encouraged to attend courses from the wide range offered by the Staff Development Office and other departments (eg, Computing). Academic staff are entitled to take sabbatical research leave (1 year in 7), and this has often provided opportunities for radical changes to research programmes. Richardson, for example, initiated his current work on single cell analysis of mRNA after a sabbatical at the Sanger Centre, and a sabbatical for Edwardson at Yale led him, via his discovery of a new protein, to explore the molecular mechanisms of exocytosis.
On his arrival in October 1999, McNaughton established a Research Committee comprising himself, Irvine, Taylor, Henderson, and Murrell-Lagnado (membership rotates). This committee serves as a focus for developing research policy, allocation of resources, and administration of the Glaxo Fund. The committee reports to bi-monthly meetings of all academic staff. A Senior Technician is responsible for all central services. HEFCE-funded technical staff are allocated to labs in a way that attempts to balance their career development with the need to provide well-serviced central facilities (animal house, cell culture, etc) and technical support in the most active labs. A priority has been to redirect such technical staff to collaborating labs (eg, Henderson/Edwardson; Hladky/Barrand) both to facilitate the collaboration and develop the breadth of expertise of the technician.
The development of joint research programmes is facilitated by holding regular meetings between groups of labs; by staff (Taylor, Thorn, Genazzani, Hinchliffe) belonging to MRC co-operatives; by research students/postdoctoral fellows having their own weekly journal club; and by a weekly departmental seminar, which is followed by an informal gathering.
A Graduate Education Committee (chair, Hiley) is responsible for admission of graduate students and for monitoring progress. The Graduate School in Biological, Veterinary and Medical Sciences was founded in 2000. It co-ordinates the many courses now provided for graduate students (in transferable as well as specific scientific skills); it maintains an electronic data base of experts from whom research students can seek advice; and it encourages best practice in supervision. All graduate students have a supervisor and a mentor (second supervisor), and maintain a student log that records meetings, progress and attendance at courses. Registration for a PhD occurs only after satisfactory progress in the first year, which is monitored by reports from the supervisor and adviser, and by submission of a dissertation followed by an oral examination. The success of our graduate training programme is reflected in the fact that every PhD student to qualify in the review period is now employed in industry or academia, the latter often supported by prestigious fellowships (see below).
Research Activities and Achievements (major funding sources shown in brackets)
Cell Signalling. Irvine (Wellcome Trust programme grant, Royal Society Chair) has pioneered studies of the role of IP4 in regulating Ca2+ mobilisation and the properties of the proteins involved. His group has cloned inositol hexakisphosphate kinase and shown it to be closely related to IP3 3-kinase; and has made the first intracellular measurements of the novel lipid, PtdIns5P. Hinchliffe (MRC Fellowship), in collaboration with Irvine, established that phosphorylation of type II phosphatidylinositol phosphate kinases (PIPkins) controls their activity and subcellular localisation. One of the kinases responsible has been shown to be CK2. Taylor (Wellcome Trust programme grant, BBSRC, BHF, Jules Thorn) developed novel methods to analyse both binding to IP3 receptors and the rapid kinetics of IP3-evoked Ca2+ release. His results establish how IP3 controls the ability of Ca2+ to regulate Ca2+ release and so provide a mechanistic explanation for the complex Ca2+ signals in intact cells. His group was the first to show that the major route for Ca2+ entry evoked by physiological stimuli was not, as commonly supposed, via a capacitative pathway. His recent work establishes that parathyroid hormone regulates Ca2+ signals by controlling transfer of Ca2+ between intracellular stores. Genazzani (Pharmacology Fellow, BBSRC David Phillips Fellow, BHF) characterised an entirely novel Ca2+ release mechanism, gated by nicotinic acid adenine dinucleotide phosphate (NAADP). He has also established a link between Ca2+ entry, activation of calcineurin and transcription of genes encoding IP3 receptors and Ca2+ pumps. Thorn’s (Wellcome, MRC) combination of electrophysiology and high-resolution Ca2+ measurements in pancreatic acinar cells has established the roles of different patterns of Ca2+ release in regulating the Cl- channels that drive fluid secretion. Thomas (Pharmacology Fellow, BBSRC) developed methods for real-time measurement of exocytosis and performed the first quantitative analyses of secretion from single pituitary gonadotrophs, showing that sex steroids potently regulate secretion. In addressing the roles of histamine (H1 and H3) receptors in neural tissues, Young (Uchida Foundation) has characterised multiple effects of histamine on Ca2+ signals and the effects of these signals on adenylyl cyclase and receptor internalisation. Smith (College Research Fellow), using quantal analyses of secretion in pancreatic ß-cells, has established the role of somatostatin and other peptides in modulating stimulus-secretion coupling. Gergely (College Research Fellow) joined the Department in January 2001 from the Wellcome CRC Institute, where she had identified an entirely novel family of centrosomal proteins that interact with microtubules
Ion Channels, Receptors and Endocytosis. Edwardson’s (Wellcome, BBSRC) interests in molecular mechanisms of exocytosis in pancreatic acinar cells led to his discovery, cloning and molecular characterisation of syncollin, a new syntaxin-binding protein on the membranes of pancreatic zymogen granules. With Koenig (Pharmacology Fellow) he has established the mechanisms and functional consequences of agonist-stimulated trafficking of muscarinic receptors. Quantitative analyses of these processes have allowed Koenig to model receptor internalisation. Edwardson (with Henderson) has also developed methods for imaging proteins by atomic force microscopy, and these are being applied to ligand-gated ion channels receptors and to proteins involved in exocytosis. Murrell-Lagnado (BBSRC, Wellcome) identified some of the key determinants of assembly of inward rectifier K+ channels, established how Na+ activates them and characterised the role of phosphatidylinositol 4,5-bisphosphate in their activation. She has also identified regions in the C-terminus of P2X2 receptors that regulate desensitization. Hladky (BBSRC) established the number of water molecules transported with each ion through gramicidin channels. His group developed a superior method, using Bayesian statistics, for fitting single-channel records from patch-clamp data. Michel, working with Humphrey (GIAP), provided definitive evidence for the presence of P2X2/P2X3 receptors on afferent nerve terminals. They cloned murine homologues of P2X4 and P2X7 receptors and identified marked species differences in the pharmacology of species orthologues. They also defined at least two functional states of the activated P2X7 receptor, consistent with its ability to switch from a conventional channel to a dilated pore. Feniuk and Sellers (GIAP), again working with Humphrey, cloned a novel splice variant of a somatostatin receptor, which is remarkable because the original variant inhibits growth, but this variant promotes growth. They identified the different transduction mechanisms of the splice variants and established the roles of other somatostatin receptor subtypes in controlling proliferation. Following his cloning of the first receptor (P2Y1) for extracellular ATP, Barnard (Wellcome) has identified and characterised further members of this divergent family and has shown that they couple directly to Ca2+ and K+ channels. Henderson’s (BBSRC) pioneering development of atomic force microscopy to study structure and function of macromolecules under near-physiological conditions has been applied to ion channels and protein-nucleic acid interactions (see under Chemotherapy).
Cardiovascular and Autonomic Pharmacology. Hiley and White (College Research Fellow) work together on endothelium-dependent mechanisms of vascular smooth muscle relaxation. They were the first to show that endogenous anandamide is not the endothelium-derived hyperpolarising-factor. Their electrophysiological measurements established the role of endothelial K+ channels in relaxation and identified important interactions between them and cGMP. Ford (Pharmacology Fellow) has shown that interactions between angiotensin receptor subtypes are crucial for protection from myocardial ischaemia-reperfusion injury. Ferguson was the first to propose, and provide evidence for, hollow muscular organs such as urinary bladder detecting hydrostatic pressure changes by releasing ATP which then acts on sensory nerves. This entirely novel proposal is now widely accepted and has recently been confirmed by purinoreceptor knockout studies by others, and his work is acknowledged as pioneering in this field. Fan (Wellcome) discovered the angiogenic activities of two structurally related ginsenosides - a novel class of angiogenic steroids that may promote wound healing. Callingham (grant from Papworth hospital) has established that vascular adhesion protein-1 is a semicarbazide-sensitive amine oxidase enzyme and his work (with Hiley) on human blood vessels has shown that the rate of association of nitric oxide with some genetically engineered haemoglobins is slower than to native haemoglobin.
Neuropharmacology. McNaughton (BBSRC, MRC, Wellcome) has characterised a modulation of the photoreceptor synaptic Ca2+ conductance by arachidonic acid. He has developed two new fields: Ca2+ signalling in astrocytes and endothelial cells, where he has characterised mitogenic actions of a novel lipid bound to albumin; and the neurobiology of nociceptors, where his group discovered ion channels gated by painful levels of heat. Morton (programme grant from Hereditary Disease Foundation) has developed a battery of behavioural, electrophysiological and cytochemical tests to study the effectiveness of therapies in several mouse models (including transgenics) of Huntington's disease (HD). She has shown an essential role for dopamine and impairments in synaptic plasticity in progression of HD. Richardson (Pfizer) has developed methods to examine global gene expression in single cells, allowing physiology to be linked with gene expression in single neurons. This work attracted a JREI award with Morton and Barrand for a laser-capture microscope. Young (Uchida Foundation) was the first to demonstrate a regulatory role for H3 histamine receptors in the dopamine-dependent ‘direct’ GABAergic pathway through basal ganglia.
Chemotherapy. Waring (CRC) has identified the base pair substituents involved in DNA nucleotide sequence recognition by important DNA-binding drugs. He has evaluated the thermodynamic effects of exocyclic substituents upon the winding of DNA around the histone octamer, and discovered that the peculiar reactivity of methylated CpG steps in DNA results from electronic effects transmitted through the base pairs. Henderson (BBSRC) has provided the first real-time images of restriction enzymes catalysing DNA cleavage and thereby established that the enzymatic mechanism is not as previously supposed. Van Veen (supported by grants in the Netherlands) has shown that ABC multi-drug transporters pump amphiphilic drugs from the inner leaflet of the bilayer by a mechanism analogous to a 2-cylinder engine. Barrand (CRC, Jules Thorn) has succeeded in generating endothelial cell cultures from both rat and human brain that provide in vitro models of the blood-brain barrier. She has shown changes in expression of multi-drug transporters and Cl- channels under conditions (hypoxia/reoxygenation) that mimic stroke. With Hladky, she has shown that these cells express volume-activated Cl- channels with properties similar to CLC-3. Matthews has developed potent new pro-drug esters for the endogenous photosensitisation of pancreatic tumour cells, and has developed fluorescence correlation microscopy to allow measurement of molecular dynamics in an optically-defined volume as small as 1 femtolitre.
Achievements Relating to Aims Set Out at the Last Exercise
We have been successful in fulfilling the four main aims set out at the last review:
(i) To maintain a supportive research environment. A priority has been to provide Research Studentships for more of the high-quality applicants than can be realistically funded from outside sources. During the review period, internal funds have been used to fully fund 17 PhD studentships and to partially fund a further 7. We provided generous start-up funds (typically £70k) for newly appointed staff and Pharmacology Fellows. Technical staff posts have been supported, including the appointment of a full-time Computer Officer, an administrative post, and an animal house technician. The Research Committee (using internal review) has administered a fund for small research grants (eg, to pump-prime projects or bridge grants). We supported refurbishment of labs (McNaughton, Morton, Irvine, Van Veen, Genazzani); animal house; centrifuge and liquid scintillation counting facilities; computer suite for post-docs and graduate students; and (in 1996) the top floor extension of the building to provide a seminar room and an attractive tea room which now acts as an important social focus. The Glaxo Fund has been an important element in supporting these initiatives.
(ii) To encourage young researchers to progress towards a first permanent appointment. Our Pharmacology Fellowship scheme came into being in 1996 and, after two open competitions that attracted strong fields of candidates, we made 5 appointments between February 1997 and October 1998. Key features of the scheme are that it provides a salary for 5 years and generous (ca £70k) start-up funds; Fellows are housed within the lab of an existing member of academic staff who both serves as mentor and allows access to the facilities of the lab; and Fellows gain experience of teaching (ca 30% of normal load). We viewed this as a long-term investment, but it has already proven very successful. Murphy left for a lectureship at the Open University in March 1999. Genazzani was appointed to a lectureship in the Department in October 2000, was awarded a BBSRC Sir David Phillips Fellowship. The scheme allowed Thomas to develop demanding methods for analysis of exocytosis from single cells; that work has also attracted substantial support from the BBSRC. Koenig’s work attracted support from industrial partners, who funded a CASE Studentship and a substantial portion of the cost of a confocal microscope; she was awarded an international prize (IUPHAR Receptor Mechanisms Prize) for her work on receptor trafficking. Ford, the youngest of the appointments, has a research student and is developing his work on ischaemia-reperfusion injury; he too received an international award in 1999 (Beamish Prize for the best paper in Can. J. Cardiol.). We have also been successful in encouraging young researchers to seek external fellowships: Genazzani spent the year (1998) after his appointment to a Pharmacology Fellowship supported by a Long-Term EMBO Fellowship collaborating with Carafoli in Zurich, and later obtained a Sir David Phillips BBSRC Fellowship; others include Hinchliffe (MRC Career Development) and Berge, Gergely, Smith and White (College Research Fellowships). Our former PhD students and postdoctoral fellows have also been successful in securing prestigious fellowships to continue their careers at universities in the UK or USA: Marchant (1996), Wellcome Prize Fellowship; Patel (1995) and Marchant (1998), Wellcome Travelling Fellowships; Carter and Kidd (2000) Royal Society Travelling Fellowships; White (1996) and Berge (1997), College Research Fellowships.
(iii) Support of important, but neglected, areas of pharmacology. Callingham, Ford (Pharmacology Fellow), Hiley and White (College Research Fellow) are pursuing active programmes in cardiovascular pharmacology without large-scale external grant support. Ferguson’s work on the role of ATP in bladder control is now recognised as important (and is supported by grants from REMEDI and Research into Ageing); it would have been impossible without internal funding.
(iv) To ensure a smooth handover to the new HOD. McNaughton was appointed in early 1999 and he moved into newly refurbished lab space (funded by the University and the Departmental Glaxo Fund), which includes a confocal microscope facility, in October 1999 (Cuthbert retired in September 1999). McNaughton’s group of 5 staff and 4 research students, supported by 6 research grants (BBSRC, MRC, Wellcome Trust) was fully operational by December, and he was able to take over as HOD without an interregnum.
Major Changes since the Last Review
Apart from McNaughton’s appointment, there have been few changes to the HEFCE-funded academic staff. Genazzani was appointed to a lectureship in October 2000 (he is currently funded through his BBSRC Fellowship). His interests in Ca2+ signalling complement those of Thorn, Irvine and Taylor; he is also developing a collaboration with Waring. Van Veen was appointed to a 5-year temporary lectureship (the post freed by Genazzani) in January 2001. He brings expertise in the mechanisms of ABC transporters, which complements existing strength in multi-drug transport proteins (Barrand and Hladky). The substantial funding he had raised in the Netherlands was not transferable, but he has submitted several grant applications. Several staff have substantially re-orientated their research. Hladky now collaborates with Barrand to examine drug transporter proteins in drug-resistant tumours. Richardson has developed methods for analysing very low levels of mRNA in small numbers of cells and now collaborates with, and receives substantial funding from, Pfizer. The methods are the subject of 2 patent filings (1 with the MRC). Henderson, who was just beginning his work with atomic force microscopy (AFM) at the time of the last review, has successfully used it to analyse DNA-protein interactions, secretory proteins and ion channels. He (with Edwardson) has received 2 substantial BBSRC grants for AFM work. McNaughton has initiated a major new program of research into the cellular and molecular mechanisms of nociception. Dean was a Principal Research Fellow of the Wellcome Trust until 2000, when after a period of substantial support from Rhone-Poulenc Rorer (£1.8M,1996-9), he set up a company, De Novo Pharmaceuticals, based on intellectual property developed by his group. Dean is now Chief Scientific Officer of the company, which provides computer-aided drug design services. The University and the Wellcome Trust hold equity stakes in De Novo Pharmaceuticals.
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Copyright 2002 - HEFCE, SHEFC, ELWa, DEL
Last updated 17 October 2003
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