John Sayer Raine Award Winner 2007
1. Title and place of work and what you are doing now
I am working as a Senior Lecturer in Nephrology at the Institute of Human Genetics, Newcastle University and Honorary Consultant at the Freeman Hospital, Newcastle upon Tyne. My job is a combination of busy clinical work, including sub-specialty renal genetics clinics, as well as leading my research team at the Institute of Human Genetics.
This Institute is located in the International Centre for Life, right in the heart of Newcastle city centre, and has a unique mix of basic science and clinical researchers, NHS clinics, a science museum and commercial businesses, all on one site.
My clinical work is at the Freeman Hospital, where we have a brand new Renal Unit, with outstanding facilities for inpatient and outpatient renal care, as well as light and airy haemodialysis facilities. It has been a real delight to see the patients enjoy these new premises and it also makes a very pleasant working environment for all the renal unit staff.
My research interests cover a range of inherited diseases including renal stones, cystinosis and inherited tubulopathies. However, my main interest concerns inherited cystic kidney diseases and the range of diseases known as ciliopathies, as the primary cilium is implicated in the pathogenesis of these diseases. Using approaches that include cell culture, zebrafish and murine models my group is investigating these disorders at a molecular level in the hope of understanding further the disease mechanisms, and identifying novel therapeutic agents that may ameliorate these diseases.
2. The work that led up to the Raine award
I commenced my PhD studies in 1998 when I moved from a jobbing SHO rotation in Truro to Newcastle University. My PhD project concerned the inherited kidney stone disorder Dent’s disease, named after Charles Dent, an eminent pioneer of mineral metabolism and kidney function.
This project was my introduction to the world of genetics, renal tubular physiology and renal tubular pathophysiology. I was fortunate to have excellent supervisors in Simon Pearce, Tim Goodship and Nick Simmons who passed on their love of scientific research. I learnt that a clinical problem in patients could be examined in terms of the precise pathophysiology at a molecular level. So, I devoted myself to studying inherited diseases, where genetic insights from rapidly expanding DNA technologies (genome sequencing / linkage analysis etc) were providing, for the first time, hints at the pathogenesis of kidney diseases.
Determined to be part of this “genomic” revolution, I was fortunate enough to obtain a Clinical Lecturer’s position at Newcastle University, which allowed a period of study abroad. I spent almost 2 years with Professor Friedhelm Hildebrandt at the University of Michigan, working very long hours which resulted in the discovery of a novel gene (NPHP6) implicated in the inherited cystic kidney disease, nephronophthisis.
This discovery of a gene led to rapidly exploring the encoded protein’s location, function, interactions and effect of knockdown in model systems. These discoveries and novel data allowed some new insights into the pathogenesis of nephronophthisis and the related ciliopathy known as Joubert syndrome. The protein was expressed in the centrosomes of renal epithelial cells as well as in the connecting cilium of the photoreceptor cells of the retina.
These findings helped to explain the blindness found in patients with NPHP6 mutations. NPHP6 gene defects are a leading cause of nephronophthisis and an inherited form of blindness known as Leber’s congenital amaurosis.
3. What or who inspired this work
For the understanding of renal genetics I am extremely grateful to my boss and friend Professor Friedhelm Hildebrandt. With his help, a disease (Nephronophthisis) which has been described in renal textbooks for many decades as “unknown aetiology” has suddenly become elucidated given the paradigm that a single genetic mutation can provide useful and novel insights into the cause of the disease.
I am also indebted to Tim Goodship who suggested going to Michigan in the first place. He has always provided me with wise counsel, and he still does.
My research into inherited kidney diseases has also been inspired by many people, including brave and stoical patients and their families, a former boss (Dr David Gibbons) who insisted I should know the molecular basis / action of every drug I prescribed and encouragement from my family.
4. What the Raine award meant to you
The Raine award was a great honour given the many worthy recipients on the list. However, I accepted it as confirmation that a career in academic nephrology was possible and gave me a greater confidence, particularly in the context of funding interviews and grant panels.
It has proven to be a real springboard for obtaining funding for my research projects as it is clearly recognised as an award for emerging renal scientists.
5. How your career has progressed since
Shortly after the Raine award news I was interviewed for a Clinician Scientist Fellowship and the award gave me a new confidence in my abilities and a determination to succeed in renal research.
I am pleased to report that I was successfully awarded a fellowship which has been invaluable in establishing my own research independence, after returning from the USA. I have successfully moved into a Senior Lecturer’s post at Newcastle University and have expanded my research group and interests.
6. What implications did your findings have for clinical practice?
Understanding the molecular genetic defect in families affected by inherited diseases is a vital step towards helping the patient and their relatives understand their disease. It allows more directed disease management and treatment, screening of other families at risk and allows genetic counselling to be carried out in an informed manner. The last few years, basic science research into cystic kidney disease has been frenetic, and this knowledge has been translated into clinical trials for patients with ADPKD.
It is my hope that understanding the childhood forms of cystic kidney disease will allow therapeutic trials to be commenced in this patient group.
7. What is your most proud accomplishment?
I am still very proud of completing my PhD! It’s a real joy to spend 3 years studying a disease in such detail that you become a “world expert” in the chosen area of study. I still enjoy the thrill of telling some of my patients that I have studied their particular disease in the lab for many years and that they remain my motivation for learning more about it.
Since then, I have been extremely proud to see my students achieve PhDs in a similar way to myself and the privilege of passing on some of my knowledge and skills makes this very rewarding.
8. What is the most pressing problem in nephrology today?
Today’s nephrologists and the next generation of nephrologists will need to become experts in individualised patient care. Patients will have genetic profiles, disease risk scores and urine proteomic profiles - somehow the nephrologist will need to interpret this data set in a sensible way in order to provide the best possible care for their patients.
The genome is “solved” but hidden within this is the fine detail of gene regulation, tissue expression patterns, alternate splicing of genes and much more. This will take some smart young nephrologists a while to sort out!
9. Advice for junior trainees in the specialty
Nephrology is a fascinating specialty, and it is full of great role models – examine the list of presidents of the renal association and talk to some of them! Find a mentor, seek their advice, take a few risks. Some of the best research is directed at solving a clinical problem or question – so every patient, the patient from last week, the next patient,…. may hold a vital clue to understanding an important clinical problem.
Take the time with each patient to consider whether you can help them, and if the knowledge of how to do so or evidence is lacking then that may provide something to keep you busy for the next 30 years!
10. What plans do you have for the future?
I hope to continue expanding my basic science research alongside some translational and clinical research projects.
I am excited about the Renal Association’s “Rare Kidney Diseases” strategy and this is something I wish to get involved with. This project aims to integrate clinical care with diagnostic molecular genetics, translational research and disease registers. The NHS in the UK has the opportunity to lead the world with this type of approach.