Helen Lachmann Raine Award Winner 2003
1. Title and place of work and what doing now 
I’m a Senior Lecturer and Honorary Consultant in amyloidosis and renal medicine at the National Amyloidosis Centre (NAC), University College London Medical School, Royal Free Campus. My job is, to my mind, a very rewarding combination of clinical and research. I participate in a general nephrology clinic and care for a satellite dialysis unit which is my contribution to the core renal medicine which goes on at the Royal Free.
My specialist interests are amyloidosis and a group of rare genetic disorders of innate immunity which cause severe systemic inflammation, the inherited periodic fever syndromes or autoinflammatory diseases. I spend 80% of my time in the NAC and also see children in joint clinics at Great Ormond Street. The NAC is centrally funded by the NHS to provide diagnostic and management advice for patients with amyloidosis and we assess about 50 patients a week. It is a lovely place to work – partly because it really is lovely after a recent refurbishment but mostly because of my colleagues.
Amyloidosis is a multisystem disease so the unit consists of consultants from haematology, rheumatology, and cardiology as well as the two nephrologists in addition to excellent multi-disciplinary input from specialist nurses, echo cardiographers, radiographers, genetic and histology technicians.
My research remains clinical and at the moment is focussed on looking at how to improve the outcome in patients with systemic amyloidosis especially AA amyloidosis, a complication of chronic inflammation which causes proteinuric renal dysfunction and untreated progresses to end stage renal failure and death.
I’m particularly interested in looking at new therapeutic agents and clinical trials. The inherited fever syndromes now take up an increasing amount of my time. I can’t claim to have ever planned my career – I’ve be very fortunate in a series of happy accidents, but I never imagined that, having trained as an adult nephrologist, I would end up spending a fair proportion of my time as a pseudo paediatric rheumatologist seeing children and young adults with fever syndromes. These rare diseases cause recurrent attacks of fever and severe pain and can eventually result in AA amyloidosis and renal failure. Understanding their genetic basis has resulted in much better understanding of innate immunity in general and many of these patients can have completely normal lives when treated with the new generation of biologics which block specific cytokines.
2.Work led up to Raine award
This was studies in a large population of patients with systemic amyloidosis. We found that hereditary systemic amyloidosis was remarkably common and could not always be distinguished clinically from AL amyloidosis.
This meant that, even the presence of a monoclonal gammopathy, genetic testing is often necessary to correctly type amyloidosis. Accurate diagnosis is of fundamental importance in the management of amyloidosis as current treatments are largely directed at reducing the supply of circulating amyloid precursor proteins and chemotherapy; the treatment for AL amyloidosis is not at all useful in hereditary amyloidosis. At the time treatment of AL amyloidosis was difficult to assess because of the lack of robust short-term parameters for measuring efficacy. Measurement of free light chains by the ultra sensitive freelite (FLC) assay has transformed the management of these patients and we were the first to make use of these technique. I demonstrated that reduction in circulating levels of FLC following treatment provides a valuable prognostic indicator for clinical outcome in the longer term and FLC assays are now used worldwide to monitor and tailoring cytotoxic treatment in patients with systemic AL amyloidosis.
3. What/who inspired the work
My first memorable encounter with amyloid was in my pathology final exams – and that awful feeling of realising that the question has a very specific point but being total unable to recognise it let alone say anything sensible.
A more clued up friend told me the answer was amyloidosis afterwards. Years later I heard Mark Pepys give a really inspiring lecture about amyloidosis in which he moved smoothly from patients with rare diseases to cutting edge research and so when Steve Powis pointed out to me that the unit was looking for a clinical research fellow I went to talk to then.
I started working for Philip Hawkins three months later and never left. Philip has certainly provided me not just with encouragement but an education about rare diseases, clinical skills, clinical research and how to think carefully and critically about problems. He also taught me that intellectual generosity always pays off whilst sloppy thinking doesn’t. The former by example, the later by constructive criticism!
4. What Raine award meant
I had diverged off away from mainstream nephrology into a distinctly minority interest in the form of amyloidosis – a multisystem disease which few had heard of and almost no one could spell. Although I had greatly enjoyed my time as a research fellow I was a little anxious about my future ability to stay in a research oriented environment and to compound matters I was doing clinical research at a time when all my friends were busy with ‘real’ research in the form of laboratory based projects.
Receiving the Raine award was enormously flattering and encouraging as I felt it was validation that purely clinical research could result in robust and worthwhile work. As time has passed the pendulum has swung back and the importance of clinical research in both common diseases and in rare disease is much more accepted.
5. How has career progressed
Well I haven’t moved away from the hospital where I started my renal training or the department where I did my thesis – so geographically not at all!
Professionally I’m now a Senior Lecturer and continue to work and publish on amyloidosis and inherited fevers. It is a very exciting time with the potential for new therapeutic strategies targeting amyloid deposits as well an explosion in our understanding of the defects in innate immunity which underlie the fever syndromes and an ever increasing arsenal of specific biologic therapies targeting different cytokine pathways to use to treat the patients.
6. What implications for clinical practice
Reverse translational medicine – taking rare patients with unusual diseases and trying to understand what is going on and find better treatments is deeply satisfying.
Over the time I have been involved in amyloidosis there has been recognition that typing of amyloid is vital and the techniques we now use have evolved to include immunohistochemistry, genetic sequencing and laser dissection with mass spectroscopy.
The importance in controlling amyloid fibril production has become clearer and our ability to monitor underlying disease activity has been radically changed by the availability of better assays whilst the treatment arsenal had been enormously widened with the new generation of chemotherapeutic agents such as bortezomib and lenalidomide in AL amyloidosis and in AA amyloidosis the development of biologics targeting not just TNF or B cells, but now IL-1 and IL-6. The inherited periodic fever syndromes were largely a group of very rare and untreatable diseases of unknown pathogenesis when I started my research.
The advances in understanding their pathogenesis has been one of the most exciting developments in medicine recently and the ability to offer patients with chronic symptomatic diseases truly effective treatment for the first time is unbelievably rewarding at both the intellectual and emotional levels.
7. What is most proud accomplishment
I don’t really know – most times that the work has turned out to be really exciting the discoveries have evolved relatively slowly and these have always been group efforts. I can’t claim to have ever had a eureka moment but a couple of discoveries have changed clinical practice around the world. Even if it’s limited to very rare diseases it’s always a nice feeling to have had an insight that really changes the understanding of a disease and how it’s managed.
The realisation during my research that inherited systemic amyloidosis was common and frequently misdiagnosed as AL amyloidosis was wonderful – and obviously getting my first New England Journal paper whilst still a clinical fellow was pretty nice. Giving the initial patient with a previously untreatable periodic fever syndrome a trial dose of an IL-1 blocker (which I must confess was Philip’s idea not mine) and seeing him discover what being normal felt like within 6 hours was a pretty special moment.
It’s not often that as doctors we cure someone and being involved in the astonishing story of the finding of how IL-1 production is regulated by the inflammasone and the subsequent drug trials of a variety of molecules which interfere with the IL-1 pathway has been an amazingly satisfying example of reverse translational and then translational medicine at their very best.
8. What is the most pressing problem in nephrology today
Clearly this is something everyone has their own take on. One of my current worries is the extremely bureaucratic and risk averse environment for clinical research at present. There is a terrible paucity of good trials base evidence for much of routine our practice in nephrology – and the difficulties and expense in setting up clinical trials at present make me pretty gloomy about how we can solve this.
9. Advice for junior trainees
I think general advice is always difficult to give and the really good specific advice I’ve got in my career has often bit uncomfortable!
That said – enjoy medicine, not all the time obviously but at least most of the time.
10. What plans for the future
We are just opening a new NCG funded treatment programme for patients with a rare inherited fever syndrome, cryopyrin associated periodic syndrome CAPS) and I am running and developing studies in the other fever syndromes. Generic anti amyloid treatments for the first time are beginning to look like a real probability for men as well as mice.
So in general it’s an exciting time ahead.