VOLUME 3 - ISSUE 3 - PHARMACOLOGY AT UNIVERSITY COLLEGE LONDON

The Department last hosted the Winter meeting of the BPS in 1991. It now returns at a very appropriate time, the centenary year of the formation of the Pharmacology Department at UCL in 1905.

University College was founded in 1826 as a secular institution to provide education for all who could benefit by it, irrespective of creed, personal wealth, race or social class. This was an unusual stance to take at the time, quite distinct from the beliefs that pervaded Oxford and Cambridge . Even in these very early years, medical sciences, as we have now come to know them, were prominent and the first Professoriate at UCL included A T Thompson as Professor of Materia Medica and Pharmacy. A subsequent holder of this post was Sydney Ringer (1878-87), who was most noted for his work on the isolated beating heart and the systematic design of salt solutions able to prolong its viability, together with his seminal ‘Handbook of Therapeutics’. The fundamental nature of calcium for cardiac muscle contraction was an important result of Ringer’s work and led to the development of the now immortal Ringer’s salt solution, familiar to many gener-ations of pharmacology and physiology undergraduates.

With the founding of the Institute of Medical Sciences in 1905, the Department of Pharmacology was established - the first such department in England, housed at that time in a single room - with A R Cushny as its first Professor. Cushny was very interested in optical isomerisation and he reported on an early clinical trial using hyoscine isomers which was later analysed by Student in his now seminal work, ‘the probable error of the mean’. Cushny was succeeded in 1919 by A J Clark, the first pharmacologist who inculcated a quantitative aspect into pharmacology by studying in detail and describing the principles of the relationship between the concentration of a drug and its effect at a receptor. In 1923, while at UCL, Clark wrote his textbook on “Applied Pharmacology” – subsequently updated many times by others in the department and still extant in the form of the standard textbook “Pharmacology” by Rang, Dale, Ritter and Moore , which itself is in its 5th edition. Clark placed great emphasis on the quantitative description of data, an emphasis which we still take very seriously at UCL Pharmacology to this day, indeed, a quote from Clark’s book on “The mode of action of drugs on cells”, published in 1933, has clear present-day resonance:

“In the first place, there is no advantage in fitting curves by a formula unless this expresses some possible physico-chemical process, and it is undesirable to employ formulae that imply impossibilities. It is a question of finding a few systems so simple that it is possible to establish with reasonable probability the relation between the quantity of drug and the action produced…”.

Clark ’s successor, E B Verney (1926-34), was noted for his work on the kidney, leading to the discovery of antidiuretic hormone or vasopressin. Verney was succeeded by J H Gaddum (1935-38). Gaddum was also an enthusiastic advocate of quantitative methods and formulated the very first principles of competitive antagonism. Subsequent holders of the UCL Chair in Pharmacology were Frank Winton (1938-61), another renal physiologist, and Heinz Schild (1961-1973). Schild’s contribution provided an additional legacy for quantitative pharmacology by developing methods for measuring and assessing drug antagonism, culminating in the widely used pA2 measurement and the ‘Schild plot’, for determining the affinity of an antagonist for a receptor. He was also an authority on histamine and allergic reactions. He was followed by James Black  (1973-78), who received the Nobel Prize for his seminal discoveries of b-blockers and histamine H2 receptor antagonists.

In more recent times, the receptor-ion channel core interest of the Department came to the fore under the leadership of Humphrey Rang (1979-1983) and Donald Jenkinson (1983-1987). My predecessor as Head of Department was David Brown (1987-2002), who discovered the acetylcholine (muscarinic)-sensitive potassium channel (M channel) and led the Department during one of its most formative eras when it became clear that advances in technology, particularly electrophysiology and molecular biology, enabled more and more incisive experimental design by which the properties of single receptors and ion channels and the actions of drugs on these could be discovered. In 1987 University College and the Middlesex Hospital School of Medicine merged to form the University College and Middlesex School of Medicine, in which the two Departments of Pharmacology were incorporated into a single Department on the UCL campus. David Colquhoun held the original UCL (A J Clark) Chair and David Brown held the Astor Chair of the Middlesex Hospital Medical School , while I hold the Schild Chair of Pharmacology. In 1999, UCL merged with the Royal Free Hospital School of Medicine. The Department is now almost entirely based on the UCL campus in the Medical Sciences Building and Medawar Buildings , and has recently gained valuable extra space in the new Andrew Huxley Building funded by a joint infrastructure award from the Wellcome Trust.

The Department has maintained a very strong research record. It is the only Department of Pharmacology in the UK to have consistently achieved the highest rating in all of the last four research assessment exercises. The core of our research is focused around the role and function of receptors and ion channels in neuroscience. Principally, this involves the study of receptor/channel mechanisms, their modulation both in vitro and in vivo, and their involvement in synaptic transmission and signal transduction pathways. My own group specialises in the molecular neuroscience of GABAA and glycine receptors to understand how these receptors operate in healthy and diseased neural tissues at the level of single proteins and in more intact systems by studying inhibitory synaptic transmission. Stuart Cull-Candy continues his internationally renowned work on excitatory synaptic transmission with Mark Farrant; and in a similar vein, Annette Dolphin and her group continue their outstanding work on calcium channel function and regulation. Alasdair Gibb continues quantitative receptor studies on NMDA receptors, studied at the single channel level, in relation to how calcium ions, calmodulin and calcineurin modulate the receptor. Lucia Sivilotti is using high quality single channel recording and, in collaboration with David Colquhoun, is establishing a very plausible and workable model for the operation of glycine channels. Martin Stocker, Guy Moss and Dennis Haylett are probing the properties of calcium-activated potassium channels and, in collaboration with Imperial College, Guy Moss is pioneering the use of scanning ion microscopy to record single channel currents from imaged presynaptic nerve terminals, something that a few years ago would have been considered impossible. David Brown continues to progress his internationally leading work on M channels. David Colquhoun has made significant impact on the analysis and interpretation of single ion channel currents and receptor mechanisms over many years. His suite of programmes offers the most powerful methods to deduce mechanistic detail which are proving invaluable in gaining insight as to how ion channel receptors actually operate.

Using more neurochemically based methods, Neil Millar continues to dissect the function of neuronal nicotinic acetylcholine receptors in addition to investigating the actions of insecticides that target these receptors in insects, whilst Talvinder Sihra’s research concentrates on the presynaptic nerve terminal, concerned mostly with mechanisms that  regulate transmitter release.

A second grouping in the Department concerns a more integrated systems approach. Tony Dickenson has received numerous awards for his work on mechanisms of pain and his group bridges the often exaggerated gap that is perceived to lie between basic and clinical sciences. Clare Stanford takes a more psychopharmacological approach to the study of anxiety, particularly relating to monoaminergic transmission. Ralf Schoepfer spans several areas from the molecular to systems with his interests in learning and memory mechanisms from the synaptic gluta-mate receptors to gene knock-outs and whole animal behaviour. Andrew Ramage is our only member based at the Royal Free Hospital and he concentrates on the control of autonomic nervous system function particularly by monoaminergic transmission. The final grouping in the Department is focused on research in immuno-pharmacology. John Foreman and Dean Willis are studying the roles of kinins as inflammatory mediators, and the roles of heme oxygenase and NADPH oxidase in inflammation, respectively.

The Department prides itself on being a research-led university teaching Department which undertakes a full BSc teaching programme in Pharmacology as well as a joint degree with Physiology, in addition to teaching pharmacology to medical students. The Department supports a full laboratory teaching programme to instil the major elements of practical pharmacology to all our students. To achieve this, we rely on the dedication of the staff, supported by know-ledgeable and professionally committed technical staff. At the postgraduate level, the Department participates in the Wellcome Trust 4-year Neuroscience degree programme, a similar 4-year MRC programme in Biomedical Sciences, and the CoMPLEX 4-year PhD programme whose mission is to enable mathematical and physical sciences students to undertakes research in the biological sciences. These schemes operate in addition to our regular 3-year PhD studentships.

So much for the past and present of UCL Pharmacology. What about the future? The outlook is promising and bright. New appointments are joining us to enhance our work on potassium channels and also open a new vista into the cystic fibrosis transmembrane regulator. The opening of the Andrew Huxley building has given the Department a fresh look, which has been helped by significant SRIF awards to refurbish much of our other infrastructure to the standards expected of the 21st century. The recent calls by research councils for more integrated science around the themes of integrated physiology, systems biology and more translational science, all include substantive elements of what we recognise as pharmacology, so the future should be looked on with enthusiasm. Any clouds? Well, yes. In any organisation where funding is constrained there will be clouds. Should we remain as a Department or become part of a larger division? Should we embrace ‘omics,’ and disease led thematic groupings? The answer to these questions is, of course, yes. They are already happening for very good scientific reasons, but should this spawn a rearrangement of the way we work? Organizational structures rarely foster integrated science per se. This is the preserve of talented individuals with a capacity and need to collaborate. Of course, we can place people in the same area and hope that sparks fly, but how big is that area to be, will it encompass basic scientists and clinicians and what about the mathematical and physical sciences? Collaborative arrangements are by their very nature highly dynamic: what is suitable today may be obsolete tomorrow. Do we therefore embark on future structural re-arrangements? What is clearly important is that we should all ensure that there are no barriers to scientific integration, particularly when presented with suggestions from aspiring individuals or groups. After all, it is becoming quite difficult to define the edges of pharmacology: so many techniques are required from what used to be regarded as other disciplines. The debate regarding the best way to achieve this will no doubt continue.

Trevor G Smart
Schild Professor of Pharmacology & Head of Dept of Pharmacology, UCL