Abstract
Dr David Bennett received his MB PhD qualification from the United Medical and Dental Schools of Guy‘s and St Thomas‘ London (UK) in 1999. He undertook an intercalated PhD studying the role of neurotrophic factors in sensory neuronal development and plasticity in the department of physiology under the supervision of Steven McMahon and John Priestley. Subsequent work investigated the importance of neurotrophic factors in the response to nerve injury. Subspecialty training in neurology took place principally in London at the National Hospital for Neurology and Neurosurgery, King‘s College Hospital, and Guy‘s and St Thomas‘ NHS Trust. Since 2009, Dr Bennett has been a consultant neurologist at King‘s College Hospital and provides a specialist clinical service for the investigation and treatment of peripheral neuropathy and neuropathic pain. He is currently a Wellcome clinical scientist and his research focuses on understanding the neurobiology of nerve injury and the development of neuropathic pain. He is a member of the Wellcome Trust-funded London Pain Consortium and Vice-Director of the ‘Europain‘ Investigational Medicines Initiative. He is also an Associate Editor of Pain Management.
Q What led to your interest in peripheral nerve injury?
Much of my PhD was related to trying to prevent the deleterious effects of nerve injury through the provision of exogenous neurotrophic factors. This sparked my interest in plasticity within the peripheral nervous system and the generation of neuropathic pain. When training as a clinical neurologist I found peripheral neuropathy and neuropathic pain particularly interesting. These are common conditions with significant morbidity and current therapy is inadequate. Peripheral neuropathy intersects with many other branches of medicine, for instance diabetology, oncology and immunology, making it an extremely varied subspecialty. The clinical examination is focused and still a vital part of patient assessment, whichh is one of the joys of neurology. Furthermore, the last decade has seen significant advances in our thinking about nerve injury and neuropathic pain from both a scientific and clinical perspective, meaning that this is an evolving area.
Q Are there any particular scientists you have worked with who have had an impact on the path your research has taken?
Steve McMahon has always been a good mentor and friend, and we continue to work together as part of the London Pain Consortium Citation[101]. I spent some time as an undergraduate working with Pat Wall and was impressed by the breadth of his knowledge, the fact that he was always excited by new problems and his enjoyment of lively discussion and controversy. I have, in some sense, had dual scientific and clinical training and have had the good fortune to train with some brilliant clinical academics including Peter Rudge and John Scadding at the National Hospital for Neurology and Neurosurgery (London, UK) and Richard Hughes at Guy‘s Hospital (London, UK). Not only did I receive excellent teaching in clinical problem solving but also the interpersonal skills needed to manage chronic disabling neurological problems such as neuropathic pain. I am now part of the collaborative effort of the London Pain Consortium, funded by the Wellcome Trust, which enables me to interact both with leading clinicians and scientists with an interest in pain. Our aim is to tackle some of the key questions in pain research in a multidisciplinary fashion.
Q In your recent publication in GliaCitation[1] you build on your work investigating axoglial signaling following nerve injury. Briefly, could you summarize your findings?
I have been interested in the means of communication between injured neurons and glia both within the peripheral nervous system and the CNS. It is now well established that, following peripheral nerve injury, the phenotype of microglia within the dorsal horn of the spinal cord changes: they proliferate, release cytokines and undergo morphological change, and actively contribute to the development of neuropathic pain. I have been studying the role of the molecule neuregulin-1, which is released by damaged primary afferents and which can drive the proliferation and cytokine release of microglia, acting as a trigger for this injury response. We discovered that the effects of neuregulin‑1 following receptor activation were mediated by a particular signaling pathway – the ERK–MAPK pathway. Blocking such signaling could reduce both the functional change in microglia and the development of neuropathic pain.
Q What are the clinical implications of this research?
It is an extremely interesting concept that glial cells are not just ‘passive bystanders‘ but may actually be driving neuropathic pain. There are a number of steps that need to be taken before this can be translated into clinical benefit. Most importantly, we need to show that glial activation actually occurs in humans in a broad range of neuropathic conditions; this will require further pathological and possible imaging studies, for instance using PET ligands to localize microglial activation. Second, we need to find a means to selectively block microglial activation. Inhibition of neuregulin-1 signaling is possible; however, this molecule is also important in relation to cardiac function and so this would not be without toxicity. Therefore, significant further research is needed before a pain therapeutic emerges based on inhibition of microglial function.
Q Your research also involves the study of channelopathies involved in inherited pain syndromes; what insight can these rare conditions give in the study of pain?
My interest in this area happened serendipitously when I was asked to clinically review a family in Columbia with a heritable episodic pain syndrome affecting the upper body, which was found to be due to a mutation in the ion channel trpA1 Citation[2]. Such heritable pain syndromes are extremely rare but do give fantastic insight into key components of pain signaling. An example is the voltage-gated sodium channel NaV1.7 Citation[3], in which loss of function mutations cause congenital inability to experience pain and gain of function mutations can cause eyrthromelalgia or paroxysmal extreme pain disorder. One of the great advantages of studying such clinical syndromes is the detailed phenotyping of sensory function that can be performed in humans compared with animal studies. We are now also beginning to probe some of the imaging correlates of the pain experienced by such patients.
Q What are the next steps for your research?
I hope to remain working on the interface between clinical problems and basic research. I will continue to study axoglial signaling both within the peripheral and CNS following nerve injury. I hope to continue the clinical phenotyping of rare inherited channelopathies in humans. In addition, we are embarking on a larger study as part of the London Pain Consortium to understand genotype–phenotype interactions in larger cohorts of neuropathy patients and to try and understand why only certain patients develop chronic pain.
Q How is your time balanced between your clinical & research work?
‘On a knife edge‘ would be the honest answer, as both exert a considerable pull. I spend approximately two-thirds of my time in research and a third seeing patients. As much as possible, I attempt to have entire days for clinical work or research. Of course, there is a certain overlap between these two spheres, for instance some of my patients will be involved in research studies and it can be extremely satisfying when clinical observations inform research and vice versa.
Q Finally, what do you think will be the hot topics in pain management in the next few years?
Biological therapies are now well established in oncology and rheumatology, and I think that we will see extension into the field of pain. The use of anti-NGF treatment for osteoarthritic pain is an exciting development Citation[4]. ‘Individualized medicine‘ is an aspiration of many branches of medicine. There is now significant effort in trying to group patients according to their sensory symptoms and abnormalities on quantitative sensory testing. Patients may ultimately be defined, not in terms of the etiology of their disorder, for example diabetic neuropathy or postherpetic neuralgia, but by the particular constellation of sensory abnormalities that they demonstrate. It is hoped that this may reflect particular pathophysiological mechanisms. The acid test of this hypothesis will be whether grouping patients in this fashion can inform patient choice. The other potential advance in this field is the huge developments in genomics, which may be used in a personalized fashion to predict both pathophysiology of a chronic pain state and, potentially, drug efficacy.
Financial & competing interests disclosure
D Bennett receives research funding from the Europain Investigational Medicines Initiative, which is a Public–Private Partnership between the pharmaceutical industry and the EU. D Bennett has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Additional information
Funding
References
- Calvo M , ZhuN, GristJ, MaZ, LoebJA, BennettDL: Following nerve injury neuregulin-1 drives microglial proliferation and neuropathic pain via the MEK/ERK pathway.Glia59(4) , 554–568 (2011).
- Kremeyer B , LoperaF, CoxJJ et al.: A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome.Neuron66(5) , 671–680 (2010).
- Fischer TZ , WaxmanSG: Familial pain syndromes from mutations of the NaV1.7 sodium channel.Ann. NY Acad. Sci.1184 , 196–207 (2010).
- Lane NE , SchnitzerTJ, BirbaraCA et al.: Tanezumab for the treatment of pain from osteoarthritis of the knee.N. Engl. J. Med.363(16) , 1521–1531 (2010).
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