PRIZE FELLOWS 2008

Dr Simon Bullock

MRC Laboratory of Molecular Biology

Cambridge

Simon received his first degree in Molecular Biology and Biochemistry at the University of Durham. He subsequently joined Rosa Beddington’s lab at the National Institute for Medical Research, Mill Hill, as a Ph.D. student. Simon’s work at NIMR focussed on genetic pathways controlling kidney morphogenesis in mammals. A growing interesting in the cell biological basis of development led him to work on a more tractable model organism — the fruitfly  —  and a post-doctoral position with David Ish-Horowicz at Cancer Research UK, London. Simon’s work with David provided evidence for a widespread mechanism for moving a subset of messenger RNA molecules to specific destinations within the cell, thus giving spatial control to the synthesis of their protein products. 

Simon moved to the Cell Biology division of the Laboratory of Molecular Biology in late 2004 as a junior group leader. His research programme in Cambridge has focussed on understanding the detailed molecular mechanisms by which the sorting of cellular components is controlled. In particular his group are trying to understand how tiny molecular machines, known as cytoskeletal motors, are able to recognise different “cargoes” and deliver them to the appropriate destinations. It is vital to have an in-depth understanding of these processes because bacteria and viruses frequently exploit these motors during infection, and because defective motor transport is implicated in several neurodegenerative diseases.

Using a combination of fly genetics, biochemistry, and advanced microscopy, Simon’s group have discovered new links between cargoes and motors, as well as a novel mode of regulation of motor transport by the cargo itself. In the future he and his colleagues will also use structural and biophysical approaches in order to reveal the detailed molecular workings of model motor complexes. The long-term aim is that the findings will help inform efforts to improve diagnostics and therapies for disease processes involving these fascinating proteins.

Dr Rebecca Fitzgerald

Hutchison-MRC Research Centre

Cambridge

Rebecca Fitzgerald studied Medicine at Cambridge University and gained her MD in 1997 following a period of research at Stanford University, California, with Professor George Triadafilopoulos.  Her postdoctoral training took place at the Department of Adult and Paediatric Gastroenterology, St Barts and The Royal London School of Medicine and Dentistry with Professor Michael Farthing funded by an MRC Clinician Scientist award. She is now an MRC Programme Leader at the Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge and Honorary Consultant in Gastroenterology and General Medicine, Addenbrooke’s Hospital Cambridge. 

Cancers of the oesophagus including those at the junction with the stomach (gastro-oesophageal junction) have a very poor prognosis because they tend to come to medical attention at an advanced stage. However, many of these cancers have a precursor, or pre-invasive, lesion and hence survival from these cancers could be dramatically improved if we could intervene early. The oesophagus provides an ideal opportunity to study the factors important in the natural history of cancer from the eearliest stages. Firstly, the oesophagus can be assessed easily using a fibreoptic instrument called an endoscope. Secondly, there is a well defined metaplasia-dysplasia-adenocarcinoma sequence in which the squamous epithelium of the distal oesophagus is replaced by a columnar-lined oesophagus called Barrett’s oesophagus in people who have reflux of gastric and duodenal contents. 

The specific issues being addressed by Rebecca’s research programme are: 1) Can we identify high-risk groups for the development of Barrett’s oesophagus and oesophageal adenocarcinoma? 2) Can we understand the molecular pathogenesis of oesophageal carcinogenesis, using a combination of in vitro cell biological assays and genomics, and apply this understanding to clinical practice? 

To address the first question we are assessing molecular changes at the level of the tissue. In order for molecular biomarkers to be applied clinically for population screening and surveillance the search for biomarkers needs to be combined with development of a robust, cost-effective assay. In a pilot-study we have demonstrated the feasibility of a non-endoscopic sampling method of the oesophagus, using a capsule sponge device. We are now evaluating the role of this method for screening within primary care (Barrett’s Esophagus Screening Trial, BEST). This trial of 500 individuals with heartburn symptoms explores the issues around recruitment, acceptability, economics and sensitivity and specificity of the test as a prelude for a larger trial. In parallel, we are evaluating biomarkers that predict prognosis for patients with Barrett’s oesophagus and associated adenocarcinoma. 

For the second aim we are utilising human model culture systems (ex vivo and in vitro) that we developed previously, to evaluate the cell of origin of Barrett’s oesophagus and the cell signalling pathways involved. Our previous work has suggested that the cell microenvironment may be an important determinant of cell phenotype. Most of this work has focussed on the luminal factors (acid, bile) and more recently we have demonstrated the luminal nitric oxide can induce DNA damage. We are now evaluating the role of the stroma which  in combination with the lumen may be an important determinant of cell fate and malignant potential. This will pave the way for studies to examine whether cancer progression can be altered by manipulation of these microenvironments.

Dr Holger Gerhardt

Vascular Biology Laboratory

London Research Institute

Cancer Research UK

Holger studied Biology in Darmstadt and Tübingen, where he specialized in Neurobiology. Holger developed a particular interest in glial cell biology and neurovascular interactions, working on development of the blood-brain barrier in the lab of Hartwig Wolburg at the Institute of Pathology in Tübingen. Holger was then part of the Graduate Programme in Neurobiology there (Graduiertenkolleg Neurobiologie) for two years and received his Ph.D in Cell Biology in 2000. In 2001, he was awarded the Dissertation Prize of the Reinhold-und-Maria-Teufel-Stiftung, Germany. Holger received a long term Fellowship from the European Molecular Biology Organisation, (EMBO) to join the lab of Christer Betsholtz at the Institute of Medical Biochemistry, Göteborg University, Sweden for his post-doctoral studies in vascular biology. He became head of the Vascular Biology Lab at the London Research Institute, Cancer Research UK in 2004 and in 2007 Holger was awarded membership of the EMBO Young Investigator Programme.  

Holger’s primary research aim is to advance our understanding of how guided vascular patterning is achieved during sprouting angiogenesis. During his post-doctoral research work before starting the Vascular Biology Lab at the London Research Institute, Holger introduced the concept of endothelial tip cells leading the vascular sprout during guided angiogenesis. In simple terms, it describes the functional specialization of endothelial cells into those that lead and guide the sprout very similar to an axonal growth cone, extending long filopodia with guidance receptors into the surrounding tissue, and those that follow the leader and form a stable new vascular tube. This concept has now proved to be most influential, not only for his own independent research, but also for the wider field of angiogenesis research in general. It has transformed the way vascular biologist look at the growing vasculature, and enabled a new focus on the function and behaviour of individual cells and their coordinated interaction with each other and the surrounding tissue. By asking questions such as what regulates the speed and directionality of the migration of tip cells, and what determines the rate of proliferation of the stalk cells, Holger and his team aim to learn about selected events and individual control mechanisms. His recent work illustrated two fundamental principals of how growing vessels are patterned, 1) by growth factor gradient dependent regulation of the balance between tip cell migration and stalk cell proliferation, and 2) by regulation of how many tip cells are formed through a mechanism known as lateral inhibition. In collaboration with other groups Holger aims to develop a deeper understanding of the control at the systems level. Ultimately, through understanding the basic principles and molecular control of normal regulated vascular patterning, this work will help to define what goes wrong in pathologies where patterning is defective. As part of Holger’s continued research supported by the Lister Institute, his lab will investigate possibilities to selectively target tip cells for refined anti-angiogenic therapies.

Dr Juan Martin-Serrano

School of Medicine

King's College London

I graduated in Molecular Biology at the Universidad Autonoma de Madrid.  As a PhD student at the Hospital 12 de Octubre, I studied the specific killing of HIV infected cells by a chimeric version of diphtheria toxin.  I then joined the laboratory of Paul Bieniasz at the Aaron Diamond AIDS Research Centre (Rockefeller University) in New York and whilst there I became interested in the cellular mechanisms that facilitate late events of HIV-1 assembly.  Since 2004 I have run my laboratory at the Infectious Diseases Department at King’s College London School of Medicine.  

It is now established that divergent retroviruses and many other enveloped viruses recruit the Endosomal Complexes Required for Transport (ESCRTs) to facilitate budding.  Importantly, the ESCRT machinery mediates a vesicle formation event in the multivesicular bodies (MVB) that is topologically identical to retroviral budding.  On the other hand, dividing animal cells pull apart into two daughter cells during the final stages cytokinesis, a process that requires breakage of the midbody, a thin membranous stalk connecting the daughter cells.  Crucially, this membrane scission event topologically resembles retroviral budding and MVB formation.  We have recently shown that several components of the ESCRT pathway are recruited to the midbody to facilitate completion of cytokinesis, thus establishing a functional analogy between late stages of cytokinesis and retroviral budding that illuminates the final steps of animal cell division.  Conversely, it is likely that the study of the molecular mechanisms that mediate cytokinesis may elucidate fundamental aspects of HIV-1 budding.  Hence, the general aim of my research is to gain a deeper understanding of the late stages of HIV-1 replication and cytokinesis through the study of functional analogies between both processes. Understanding these processes might lead to the identification of new therapeutic targets to treat infection by HIV.