Written by the Editor
Professor Alistair Mathie, one of Metrion’s previous external speakers, gives a perspective below regarding his research into two pore domain potassium channels and his involvement in a collaborative project focused on the detection of atrial fibrillation (AF). On the latter topic, Metrion would like to offer its congratulations to Alistair and his colleagues on the Pharmacists Detecting Atrial Fibrillation (PDAF) Team. On Thursday 22nd November they were awarded a “Healthcare Pioneers” Award at the House of Commons for showcasing best practise in atrial fibrillation (AF).
Your early career involved working with some exceptionally talented scientists, culminating in your Fogarty International Research Fellowship in Bertil Hille’s lab. How did these early days influence you and your future direction as a scientist?
I think I was influenced in a variety of ways, some obvious and others that I have taken time to realise. Of course, the chance to work with scientists at the forefront of ion channel research, not long after the development of patch-clamp recording methods, gave me the opportunity to interact with and learn from experts from all over the world. Both at UCL and at the University of Washington, almost all leading researchers in the area visited to talk about their current research. It is easy to become inspired and enthused in such environments.
Working with Bertil Hille, in particular, taught me that making meaningful and reliable scientific advances is hugely difficult and that it is important to question every step one takes carefully and take as much advice as one can along the way. Gaining the confidence to ask what appear to be basic or trivial questions is an important skill. In the absence of this, it is easy to become defensive and become reluctant to accept advice and criticism, however well intentioned. In my experience the best scientists do not usually get things right first time, but most understand that this does not represent any particular failure on their part.
“Making meaningful and reliable scientific advances is hugely difficult and that it is important to question every step one takes carefully and take as much advice as one can along the way”.
I have long understood how privileged I was to be able to work in such labs and what advantages this has given me throughout my career – it is telling, perhaps, that this is the first thing you have asked me about, even nearly thirty years on. What has taken me longer to understand is how difficult it is for many others to realise the same privileges, through personal or other circumstances. It was comparatively easy for me as a twenty-something, single, slightly nerdy, white male to move to where I needed and wanted to, in order to learn and gain experience. It is clearly not so easy for everyone to make the same career decisions. I think that one of the biggest challenges we face in science, is how we afford everyone the same opportunities to develop at different stages in their career, regardless of their individual circumstances.
Two pore domain potassium channels made their first appearance in your publication record in the early 2000’s and this family of ion channels has been a clear focus of your research since this time. What stimulated your interest and what inspires you to continue this research?
Like most things in science, it was largely serendipitous. My first grant from the Medical Research Council (in the nineties, when they still funded basic/exploratory research) was to study cerebellar granule neurons to see if they have a potassium current that regulated their excitability, rather like the M current seen in peripheral neurons and initially described by Paul Adams and David Brown. After some stumbling, we managed to find a non-inactivating potassium current in these cells, which was inhibited by muscarinic receptor activation, but which in lots of ways did not really resemble an M current. Then, I think around 1996, I became aware of the work of Larry Salkoff describing a large number of four transmembrane domain (4TM), two pore domain (K2P) putative potassium “leak” channels in C. Elegans. It seemed clear that homologues in mammals must be important and could explain many of the observed leak potassium currents seen in mammalian neurons and other cells and so it has turned out. Since then, I have kept meaning to move on to other things, but K2P channels keep cropping up in different cells and processes.
During your presentation at the Metrion Biosciences External Speaker series in October 2017 you reviewed the TASK-3 mutations responsible for KCNK9 imprinting syndrome and Professor John Graham’s involvement in the off-label use of mefenamic acid (Ponstel®). Have there been any developments in this story since your presentation?
From the perspective of our research, through collaborators, we keep being informed of new patients with mutations of KCNK9 (TASK-3). About half of these have the same G236R mutation but there are now many other mutations identified in different regions of the channel. Two major complications have arisen from this. Firstly, the symptoms displayed by the patients vary quite widely both in their phenotype and in their intensity. Secondly, some of the mutations do not lead to the same functional alterations in the TASK-3 channel. As such, compounds which activate TASK3 channels may not be efficacious in all patients. At the moment, together with many colleagues around the world, we are trying to collate the information we have, both in terms of the patients and the properties of the mutated channels, to build as complete a picture as possible.
With the ongoing opioid crisis in the USA and Canada it is clear that the identification of novel, effective and non-addictive treatments for pain should be a high priority for the pharmaceutical industry. A number of two-pore domain ion channels are found in sensory nociceptive neurons, could this family of channel be the route to new non-addictive analgesics?
We think so. There are strong physiological reasons to support the hypothesis that activating K2P channels to dampen down sensory neuron firing might be a useful therapeutic strategy. My group has felt for a long time that both the number and diversity of potassium channels in humans, presents the opportunity for more selective and, perhaps, more subtle control of nerve activity. The challenge, of course, is to come up with compounds that act selectively on the channels of importance.
What are your future research plans?
Oddly enough, as I approach my dotage, I seem to have developed a whole range of research interests both with K2P channels and beyond that have rekindled my enthusiasm for research in the face of increasingly difficult funding challenges. All of these have come about through collaborations and discussions with people I enjoy talking to and working with, particularly my long-time colleague (and partner), Emma Veale.
So, for K2P channels, in addition to the KCNK9 imprinting syndrome work described above, we have projects on the role of TASK-1 channels in pulmonary hypertension (with Angel Cogolludo in Madrid) and, more generally, on the role of infection in pulmonary hypertension as part of a consortium led by my colleague and friend at Kent (Ghazwan Butrous). In a separate K2P channel project, we are about to formalise a collaboration with Paul Wright and colleagues at LifeArc to look at K2P channel activators in pain (as touched on above).
Away from K2P channels, we have started a collaboration with Marc Fivaz (supported by a Leverhulme Grant to Marc) to look at the role of bioelectric signalling in human stem cell models of cortical development and we have a couple of projects focusing on voltage-gated potassium channels.
Finally, moving away from direct ion channel research, but not bioelectricity, I am involved in a project led by Emma Veale to look at the detection of atrial fibrillation (AF) in the community and the development of novel approaches to improve AF screening and detection, supported, primarily, by Bayer. Through this latter project, I have come to realise that there are many issues around the delivery of healthcare that those of us with a background in (and mind set for) hypothesis-led research have, potentially, much to offer.
What made you choose to stay in academia rather than going into industry?
I usually answer questions like this by re-stating my enthusiasm for teaching. However, I have a couple of lectures coming up later today as I write this and my enthusiasm for the task is at a low ebb. Usually this passes once I engage with the students, so we will see. Other than that, I like the illusion of freedom that academia provides, even if the reality is somewhat different.
Do you feel that pharmaceutical companies do enough to engage with academics and embrace their findings?
I don’t think there is a lack of willingness on either side, but good, fruitful collaborations rely on building strong relationships and trust between the parties involved. This is not an easy thing to do. The more opportunities there are for industry and academia to mix, the better. As a former Royal Society Industry Fellow and thus a member of their Industry Fellows College, I think the Royal Society works hard to build these relationships and has good ideas how to do this. Closer to home, I’m excited by the efforts to link the British Pharmacological Society with the European Laboratory Research and Innovation Group (ELRIG) through their respective annual conferences “Pharmacology” and “Drug Discovery”. I am keen to attend meetings of the latter in the future.
How do you feel that the landscape of academia has changed in recent years?
There seems to be more pressure to deliver, usually measured against sets of metrics that are, at best, questionable. As a result, it seems a less happy and trusting environment than I remember. The paradox, as is true in most working environments, is that one needs management with direct working experience (in this case experience of academic research and teaching), but the longer such individuals are in management the more divorced they become from their experiences as academics. As current Deputy Dean for Science at Kent, I wrestle with this problem quite often. Time management is key, but both myself and many academic colleagues could be better at this than we are.
Why do you think ion channels have been a difficult drug target class for the pharmaceutical industry?
Historically, one of the main difficulties has been the paucity of reliable high throughput screens coupled with a lack of potential selective, lead compounds. This has changed significantly in recent years, but there has not yet been the collective mind-set to revisit viable targets armed with these technological advances.
In October 2017 Alistair gave a presentation entitled “The therapeutic potential of activators of two-pore domain ion channels” as part of Metrion Biosciences’ External Speaker Series, his presentation can be found here.
The Metrion Biosciences’ External Speaker Series was established as a forum for leading academic researchers to present their latest research to our staff and staff from other companies in the Cambridge area.
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