Theme Leads

This Department undertakes research encompassing basic and applied biomedical and veterinary sciences, ranging from molecular sciences to whole animal research, clinical science and comparative medicine. We regard this broad remit as a strength and aim to be internationally competitive at the highest level, to foster collaborations with academia and industry and to ensure that our teaching and clinical work benefit from research excellence.

Clinical Pharmacology and Therapeutics (CPT, Professor Brown), Cardiovascular (Professor Bennett) and Pharmacological Sciences (Professor McNaughton)

The wealth of distinct older drugs for hypertension, and availability of monogenic extremes as controls, allowed us to pioneer rotation – or complex crossover – studies as a method for analysing inter-individual variability in response (Brown, Lancet 1999). The resulting AB/CD rule, now taken up by NICE, led to recognition that most patients lie on a spectrum of plasma renin where a few at the extremes respond quite differently to two broad categories of drugs, but most require combinations drawn from the two categories. Reverse translation of the AB/CD rule allowed recognition of young low-renin patients as an "exceptional phenotype" model of Na+-dependent hypertension, where novel inhibitors of aldosterone secretion may be required and tested – first in cells cultured from patients with adrenal tumours, and then the whole patient. Proof-of-concept studies for novel compounds are more likely to tackle systolic hypertension, where we have no drugs, than diastolic hypertension where we have many. Ian Wilkinson uses multiple non-invasive clinical methods to study causes and consequences of age-related loss of elastic tissue in large arteries. Forearm plethysmography is a valuable, minimally-invasive method for studying novel GPCR-agonists and antagonists without exposing healthy subjects to systemic doses. In bench-to-bedside collaborations internally (Davenport) and externally (Douglas, GSK), urotensin has been identified as the most potent vasoconstrictor in human arteries, whose physiological role will be explored with a novel GSK antagonist. All TMAT trainees will do a mini-project in pharmacological science as part of their MPhil. Many will be undertaken in the Department of Pharmacology, one of the largest in the UK, and home to several Wellcome Trust-funded investigators (Irvine, Taylor, Cooper). The projects will teach essential pharmacological principles, and a range of techniques such as those used to measure receptor and second messenger activation.

Metabolic Science (Professor O’Rahilly)

The new Institute of Metabolic Science (IMS) brings together basic, clinical and population scientists in obesity, diabetes and related metabolic disease. The IMS has particular strengths in the dissection of the aetiological heterogeneity of these conditions. Commitment to 'mechanism targeted' therapy is exemplified by the dramatic demonstration of the clinical efficacy of recombinant leptin therapy in congenital leptin deficiency and ongoing exploratory trials of targeted therapy in genetically defined subgroups of patients with obesity and insulin resistance (supported by the recent MRC Experimental Medicine programme). Considerable resources have been committed to the development of resources that will be crucial for future experimental studies including a) the establishment of large cohorts of genetically characterised subjects invaluable for future explanatory therapeutic trials b) the development of state of the art methodologies to assess the impact of interventions e.g. chamber calorimetry, body composition (including Echo MRI in collaboration with GSK), appetite laboratory including neuropsychological tools), and MRS studies of muscle and liver and functional brain imaging. An example of the power of this environment is the recent publication (in Science) by Farooqi/O'Rahilly in collaboration with Bullmore (GSK) and Fletcher (Psychiatry) which used patients with genetic disorders of satiety to explore the effects of recombinant leptin therapy on the higher cognitive and neuroanatomical response to the visual presentation of food-related stimuli. This is an example of how mechanistic studies in limited numbers of highly characterised subjects can provide novel 'biomarkers' of great potential utility to anti-obesity drug development. The future success of the IMS will require a cadre of young clinician-scientists with a deep understanding of disease mechanism combined with the desire, and appropriate training, to explore novel 'mechanism-based' therapies

Neuroscience (Professor Bullmore, Professor Trevor Robbins)

Training of translational physicians with specialist expertise in Neuropsychopharmacology will capitalise on the rapid growth of cognitive neuroscience and lead to new drugs for depression, schizophrenia and addiction – currently among the leading causes of morbidity worldwide. Cambridge can provide wide-ranging senior expertise in this area via the Behavioural and Clinical Neuroscience Institute (BCNI), jointly funded by the Wellcome Trust and MRC. The BCNI encompasses preclinical and clinical groups using multi-disciplinary approaches to characterise brain systems involved in normal cognitive function and to understand how these systems are perturbed by neuropsychiatric disorders and therapeutics. The BCNI's 100-odd affiliated scientists and students study obsessive-compulsive disorder, attention deficit-hyperactivity disorder, and drug addiction; dopamine, reward and appetite; and pharmacological remediation (flumazenil, modafinil) of cognitive deficits in schizophrenia. The BCNI supports a two-way translation of concepts and techniques between studies of experimental animals and clinical experimental medicine studies, making use of various methodologies (functional MRI, human and animal PET, human and animal electrophysiology, EEG and MEG, cognitive and behavioural testing, and molecular genetics. The BCNI works closely with GSK on several projects: for instance, investigating the brain functional substrates for compulsive and addictive disorders and their modulation by dopaminergic drugs; and the effects of a marketed anti-obesity drug (sibutramine) on brain and behavioural markers of food-related reward processing in patients with obesity. TMAT trainees will be able to participate in studies using a GSK incubator drug to investigate novel indications at the interface between cognitive and metabolic medicine.

Oncology (Professor Ponder, Professor Eisen, Professor Jodrell)

The overarching theme of the new £50M Cancer Research UK Cambridge Research Institute (CRI; 2007) and the Hutchison/MRC Research centre (2001) is to take basic cancer biology to clinical application. Basic research is focussed on epithelial cell biology, transcriptional regulation, DNA replication and repair, and tumour microenvironment. This feeds into, and is supported by, strong groups in enabling technologies, which include molecular imaging, genomics, mouse models of cancer (a 'mouse hospital' has been established for preclinical studies of therapy and detection) and biomolecular computing. With the new resources from CRUK we will be a hub for testing new therapies, especially targeted treatments predominantly coming from the development programmes of pharmaceutical industries. Enhanced expertise in TMAT will allow us to extract maximum benefit for the patient at acceptable toxicity. This is particularly important in oncology where therapeutic risk benefit ratios are amongst the most challenging in medicine. There is an established clinical trials infrastructure (including an Experimental Cancer Medicine Centre grant, Caldas) and the phase I/developmental therapeutics component has been strengthened by the recent appointment of a Professorship in Cancer Therapeutics (Jodrell). Associated with this professorship is the establishment of 'core' pharmacokinetics/pharmaco-dynamics facilities within the CRI.

Therapeutic Immunology (Professor Ken Smith)

Cambridge has a strong record of delivering immunological discoveries to the clinic, including the development of monoclonal antibodies, the first humanised monoclonal antibody (Waldmann: Campath, now in wide clinical use), the first use of ciclosporin, and advanced therapeutic antibody engineering (Winter). The TMAT projects illustrated by our proposed supervisors will provide training in basic immunological mechanisms, the mechanisms of immune-related disease and early phase clinical trials of immunotherapeutics. An example of translation has been the development of techniques to predict and monitor therapeutic outcomes in patients with autoimmune disease (such as lupus) by applying RNA microarray analysis to peripheral blood lymphocytes.
In therapeutic immunology, we can be confident of having powerful new treatments, some arising out of local discovery, for which we need to find the patients most likely to benefit. The TGN1412 (TeGenero CD28 superantibody) experience highlighted the importance of novel biologicals being developed by TMAT-trained doctors in order to harness their power without hazarding the patient. The value of the Cambridge environment for training in TMAT in immunology will be enhanced by interaction with GSK, since one of the first three incubators at GSK CUC will focus on translational and therapeutic immunology.

Industrial Partner - GlaxoSmithKline (Professor Bullmore)

GSK has announced plans to initiate an Academic Clinical Development Incubator (ACDI) model for working with universities, and to pioneer these incubators in Cambridge with new compounds in three of the above themed areas: oncology, inflammation/ immunology and neuroscience. Each incubator will resource a small group of University of Cambridge and GSK scientists to plan experiments leading to clinical proof of concept of a lead compound. These experiments will provide real-life training in design and conduct of decisive clinical efficacy studies in normal volunteers and carefully selected patients, and in selection and validation of soluble or imaging biomarkers linked to biological understanding of the drug target and mechanism of action.

Supporting Information: CATO; Clinical Pharmacology Unit; School of Clinical Medicine; Medschl Webmail; Medical Library; Department of Medicine