Professor Rajesh Thakker, Fellow of the Royal Society and May Professor of Medicine at the University of Oxford, specializes in Multiple Endocrine Neoplasia 1 (MEN1) and neuroendocrine tumours (NETs). He tells us more about his career inspirations, advances, challenges and opportunities within the field, both in clinical research and practice, and how his role as Endocrine Neoplasia Syndromes Network Convenor supports his work.
What inspired you into endocrinology, and why did you then focus on neuroendocrine tumour research?
This began with a patient, as is often the case for physician-scientists. Whilst studying Natural Sciences at Cambridge, I developed an early interest in endocrinology. Later, as a registrar at The Middlesex Hospital in London, I was admitting a young woman, from A&E, with severe hematemesis due to a peptic ulcer. She also had a history of renal stones due to primary hyperparathyroidism; and further investigation showed she had a prolactinoma. All this indicated that she had multiple endocrine neoplasia type 1 (MEN1), a genetic disorder inherited as an autosomal dominant trait.
At the time, the genetic defect and the underlying molecular and cellular mechanisms causing MEN1 were unknown. Fortunately, I was then working with Jeffrey O’Riordan, who had expertise in endocrinology and calcium homeostasis, and who encouraged me to pursue research. Moreover, looking after patients with endocrine disorders led me to realise two things. First, that there were still many gaps in our knowledge of the underlying mechanisms of endocrine conditions; and second, that these mechanisms could be elucidated through the recent advances in molecular biology.
This was exemplified by an inspiring lecture, by Jack Martin, on the identification of parathyroid hormone-related peptide (PTHrP), as the humoral factor causing the hypercalcemia of malignancy. During the lecture, he illustrated the usefulness of the molecular approach to understanding fundamental disease processes. Deeply excited by this discovery and its scientific approach, I put my efforts into obtaining a Medical Research Council (MRC) clinical training fellowship, to further the understanding of the biological mechanisms involved in endocrine disorders. Since then, as a physician-scientist, I have been engaged in the investigation of the molecular genetics of endocrine diseases – a constant source of challenge and excitement in uncovering the underlying biological mechanisms that cause human disease.
Can you tell us a little about your current research and clinical work?
My current research focuses on two main areas. The first is to identify genes whose mutations are involved in causing endocrine tumours and diseases – and area where the advances of next generation sequencing have tremendously helped, and where there is enormous potential to make new discoveries and translate them for patient benefit. The second area explores the mechanisms of G-protein coupled receptor (GPCR) signaling – we have recently identified a non-canonical pathway in which signaling by the calcium-sensing receptor (a GPCR) involves endosomes. Targeting this non-canonical endosomal pathway may elucidate novel signaling targets that could be altered by pharmacological compounds.
Over the last decade or so, what do you think have been the most significant advances in neuroendocrine tumour clinical practice, and/or research?
The implementation of genetic testing has been very useful – it had a major impact in the diagnosis and management of patients with endocrine tumour syndromes, such as multiple endocrine neoplasia. Screening for these tumours, including neuroendocrine tumours, results in their earlier detection and treatment. On the research front, the introduction of many new treatments, e.g. tyrosine kinase inhibitors and mTOR inhibitors, as well as some emerging therapies such as epigenetic modifiers and gene therapy, which are in the pre-clinical stages, have been very significant.
What do you think will be the next big or important breakthrough for treatment or diagnosis of neoplasia syndromes?
The next big breakthrough for diagnosis is likely to be the advent of enhanced imaging modalities that will detect the tumours at an early stage, together with molecular biomarkers that will help their detection and monitoring. When it comes to treatments, the next big step is likely to involve emerging compounds such as monoclonal antibodies, agents targeting oncogenic pathways, radionuclide therapy and epigenetic modifiers.
What do you think are the biggest challenges faced by your clinical specialty?
The biggest challenges faced by our clinical specialty, and indeed all clinical specialties, are the difficulties in the training programmes of our younger doctors. Morale amongst the young doctors is low, and they feel undervalued. This is totally counterproductive, as we attract the brightest and most talented students into medicine, and yet the current organizational infrastructure and systems seem to thwart their talents and abilities rather than allowing them to thrive and expand and achieve their aspirations. These difficulties are due to multiple factors that include:
- lack of flexibility in training pathways;
- the rotas, which are often not provided well in advance and are rigid such that forward planning for leave is precluded, and have gaps that result in increased workload for the doctors and a strain in the provision of service;
- the absence of a clinical firm with senior doctors (consultants) that provide role models, inspiration and encouragement for the younger generation to aim high, and to support them in their careers.
All of this has resulted in diminished attractiveness for the role of the “medical registrar”, with a decrease in recruitment of top caliber doctors. We need to act fast to rectify the current situation if we are going to maintain the high excellence of our medical practice and its vital underpinning by scientific advances. To achieve this, all the learned societies and NHS need to work with the Royal Colleges to deliver on the recommendations made by the report “The medical registrar: Empowering the unsung heroes of patient care” (The Royal College of Physicians, March 2013), and thereby improve the situation for our younger doctors.
Are there any controversies in your practice area? How do you think they will be resolved?
There are many controversies in the diagnosis and management of NETs, which largely stem from a lack of adequate clinical trials that would provide evidence of their efficacy – thus, we are reliant on expert opinions that aren’t always in agreement. In rare diseases such as NETs, it would be important for experts from multiple centres to collaborate, designing studies to evaluate the methods used for diagnosis and treatments, so that the most effective tests and treatments can be implemented in a standardised manner for our patients.
What do you enjoy about being an Endocrine Neoplasia Syndromes Network convenor, and how do you think it may benefit others?
It is a privilege to work with enthusiastic colleagues at different career stages, and to have a free exchange of ideas between scientists, clinician-scientists and clinicians, all of whom have a “can-do” approach. As a convenor, I have learned a lot from my colleagues and patients – the free debate that we have helps to advance the field and provide insights into the biology of the disorders, and to explore ways of benefiting our patients.
Do you have any words of wisdom for the younger generations of endocrinologists?
Endocrinology is a fascinating discipline – it will satisfy those who are intellectually curious, yet are equally keen to apply their knowledge to a practical setting. Moreover, endocrinology embraces a diverse spectrum of biological and metabolic processes, whose dysregulation affects virtually every human disorder. Furthermore, in the UK we have major international leaders in endocrinology, and there are ample and extraordinary opportunities for young endocrinologists to get top training in clinical endocrinology and basic science. Finally, we have outstanding funding organisations such as the Medical Research Council and the Wellcome Trust, which have an excellent track record in funding research in endocrinology.
Young endocrinologists can have a wonderful future in this discipline. My advice to aspiring endocrinologists would be to not ask what endocrinology can do for you, but to instead ask what you can do for endocrinology – you will then be assured of an exciting and satisfying career.
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