Menna Clatworthy Raine Award Winner 2006
1. Title and place of work and what doing now 
Wellcome Trust Intermediate Fellow & University Lecturer in Transplantation Medicine, University of Cambridge: Honorary Consultant Nephrologist, Addenbrookes Hospital, Cambridge. Currently working at the National Institute of Health in Bethesda, Washington DC in Ron Germain’s lab.
2. Work led up to Raine award
I undertook a PhD in immunology, mentored by Prof. Ken Smith at the University of Cambridge, focusing on the inhibitory receptor FcγRIIB. This work led to a better understanding of the role of this important receptor in infection and autoimmunity (particularly SLE) and highlighted its potential as a therapeutic target in autoimmune disease.
FcγRIIB is expressed on most immune cells (notably B cells, dendritic cells, and macrophages) and controls the activation of these cells by antibody (IgG) or immune complexes. In humans, there is a polymorphism in this receptor (FcγRIIB-T232), which is found at higher frequencies in Africans and South East Asians. My work has helped to show how this polymorphism causes dysfunction of the receptor and that it contributes to susceptibility to SLE. We’ve also investigated more broadly why such an autoimmune-prone polymorphism has persisted within the gene pool, and is more prevalent in some populations. The answer to this lies in its role in controlling the immune response to infection; although FcγRIIB-T232 is a disadvantage in terms of susceptibility to autoimmunity, it’s actually beneficial and leads to a heightened immune response to some infections, particularly malarial infection. This work begins to explain how and why autoimmune-causing polymorphisms might have evolved.
3. What/who inspired the work
My first experience of basic science and laboratory-based research was as a pre-clinical medical student in The University of Wales College of Medicine, Cardiff. I decided to do an intercalated degree in Anatomy under the supervision of Mike Benjamin. I really enjoyed the opportunity for independent thought and study, and presenting my own original data and decided from there that I would likely pursue a career in academic medicine. Having completed my medical degree and move to Cambridge, I became more and more interested in immunology. It was here I met Ken Smith, whose energy, enthusiasm and breadth of immunological knowledge was inspirational. Under his supervision I was not only involved in basic science research on Fc receptors but also began to apply some of this knowledge clinically. I hope that I have also learned some of Ken’s ability to identify important scientific questions and his legendary capacity for socialising! More generally, Cambridge is an excellent academic and clinical environment and has many inspirational individuals whose example provides a constant challenge to strive to solve important clinical and scientific problems.
4. What Raine award meant
My PhD involved basic science research, and tackled broad problems in infection and autoimmunity rather than a specific question in renal medicine so it was really pleasing that its significance was recognised by the Renal Association through the Raine Award. I also felt it was important to raise my profile as a potential future academic in the Nephrology and Transplant community.
5. How has career progressed
After my PhD, I returned to the wards to complete my clinical training in Renal Medicine, initially as a Specialist Registrar and then as a Clinical Lecturer. Fortunately the latter post allowed me time to continue with laboratory research, completing some outstanding work on FcγRIIB and malaria and writing a fellowship application. In 2006 I was awarded a Wellcome Trust Intermediate Fellowship for 5 years, which I began in 2007 and included an opportunity to work in a US lab. In 2007, I was also elected as a Fellow of Pembroke College, Cambridge and enjoy teaching and supervising medical students. In 2008, I completed my clinical training and was appointed as an Honorary Consultant Nephrologist at Cambridge, with an opportunity to combine clinical work (particularly in renal transplantation) with on-going basic science research and get involved in translational projects, for example, applying my knowledge of basic immunology using B cell depletion in renal transplantation. I’ve been in Washington since April 2010 for a period of focused research, and am using some really amazing equipment here, which allows real-time imaging of immune cells in kidneys and lymph nodes. I hope this will help to clarify a number of outstanding questions in renal immunology and will provide the basis of studies which I can continue on my return to Cambridge next year.
6. What implications for clinical practice
FcγRIIB controls B cell, DC and macrophage activation by antibody or immune complexes. Thus, manipulating FcγRIIB expression and function has potential therapeutic value modulating immune responses in autoimmunity, transplantation and infection. In the last decade, B cell depletion has shown surprising efficiacy in many autoimmune diseases. Cross-linking FcγRIIB on B cells and plasma cells can result in apoptosis in some circumstances. Therefore, this receptor may be a useful target in attempts to kill plasma cells, a previously elusive cell in both autoimmunity, antibody-mediated transplant rejection and haematological malignancy.
7. What is your most proud accomplishment
As an academic, the high points have been receiving the Raine Award and the Medical Research Society Young Investigator Award for the work performed during my PhD and more recently publishing our results on B Cell depletion in transplantation in the New England Journal of Medicine. In terms of teaching, for the last couple of years I’ve been working on an undergraduate case-based textbook in Nephrology (Clinical Cases Uncovered – Nephrology), which was published in March 2010. I really enjoyed gathering together my teaching resources, and I hope that my efforts will help students understand some of the nephrological concepts with which they frequently struggle. Outside of medicine (and not that I’m competitive!) it’s hard to choose between the conversion kick which resulted in defeat of the evil dark blues, (AKA the Oxford ladies rugby team) or dancing Tango for the physicians team which beat Andrew Bradley and surgical colleagues in the “Strictly Transplant” charity fundraiser this year.
8. What is the most pressing problem in nephrology today
In nephrology, the survival of patients on long-term dialysis continues to be a major challenge, but not my particular interest.
In transplantation, although we have become very good at treating acute rejection, we have made little impact on improving long-term graft survival after the first year. There is a need to increase our understanding of the processes involved in chronic graft attrition, including the role of antibody and B cells (something which I would like to be involved in) so that there is a rationale for new therapeutic measures which may prolong the lifespan of this precious resource. As a transplant community, initiatives which combine resources (such as the current UK Genome Wide Association Study (GWAS)) will be important to achieve this. I also feel that we should be undertaking more trials nationally, so that we can come to a rapid and firm consensus on optimal management strategies.
9. Advice for junior trainees
In an era where competition for senior posts may be stiff, it becomes increasingly important for juniors to have some exposure to research. I personally think that undertaking a PhD is hugely beneficial, regardless of whether you see yourself as an academic. It helps to develop critical thinking and, in my opinion, actually makes you a better clinician. For those seriously contemplating a career in academia, then chose your PhD supervisor and lab carefully because the output of your PhD will have a big impact on your ability to secure future funding. In terms of more general advice, hard work and persistence generally pay off.
10. What plans for the future
In the immediate future, I hope that my time at NIH will yield some exciting data. It’s already been a useful experience because it’s actually very hard to focus on science when you have clinical commitments. I hope to return to Cambridge and establish my own lab over the next few years, incorporating basic science research with some translational projects, particularly in transplantation, whilst still doing some clinical work and teaching.