Professor Nikita Gamper, the ninth contributor to Metrion Biosciences External Speaker Series, gives a perspective below regarding his ion channel research focus and collaboration activities with scientists from the Hebei Medical University, China.
Q1. You currently split your time between Leeds University and your role as Adjunct Professor of Pharmacology position at Hebei Medical University in China. What influenced you to collaborate with this team of scientists?
There is quite a list of reasons actually. But most important are the following: i) robust, dynamic and enthusiastic research group at HebMU; ii) strong cohort of PhD and Masters students; iii) collegiate and friendly environment; iii) generous intramural and extramural funding; iv) booming biotech industry giving access to affordable cutting edge technologies.
Q2. Your publication history involves research into ion channels including GABAA, KCNQ (M-type), Ca2+-activated Cl–, sensory TRP channels and voltage-gated Ca2+ channels; including their modulation by protein coupled receptors (GPCRs). If you had to pick one of the above to focus your research upon what would it be and why?
Even though we do have active projects on all above mentioned ion channel families, our largest endeavour currently is focused on the role of GABAA channels in peripheral pain pathways. We think that there is a GABA-ergic gate within the peripheral somatosensory ganglia, which controls the nociceptive input to the CNS. We are now working on deciphering the cellular and molecular mechanisms of this phenomenon. I am really excited about this new line of enquiry as it may change the way we think of how somatosensory information is processed by the nervous system. Additionally, it may uncover a whole new ways of pain control.
Q3. Are there any recent advances in either scientific technology or understanding that particularly interest you?
Definitely there is a lot going on in terms of technology. I am particularly fascinated with opto/chemogenetics, novel transgenic and gene delivery approaches and a whole swarm of new ideas in microscopy (super-resolution, expansion, clarity, light-sheet imaging etc.). Of course there is also a Cryo-EM revolution which is changing structural biology at a speed.
Q4. Your research involves a range of ion channels that may regulate nociception. Asking a similar question to the one we asked Alistair Mathie in November 2018, do you believe that specific modulation of ion channels could be a route to new non-addictive analgesics? If yes, where do you see the most promise for a clinical candidate?
I believe that one key approach could be in finding a way to restrict ion channel modulators away from the CNS, such that only peripheral nerves are affected. Most pains are triggered by peripheral input; even in the cases where central sensitization plays a major part, usually peripheral input is necessary to trigger a sensation. Thus, effective analgesia could be achieved by precipitating such input using treatments that do not affect CNS. One area to look at is the fact that spinal ganglia (e.g. dorsal root ganglia, DRG) are not well protected by the blood-brain or blood-nerve barriers. Hence, one can try to target DRGs by drugs with poor BBB permeability. For instance, there is a good evidence that M-type channel activators are efficacious when applied to DRG directly in rodents. Peripherally-restricted GABA-mimetics or other drugs that dampen excitability could also be tested I suppose.
Q5. What are your future research plans?
I mentioned the GABA project already, this is one of the main activities for the immediate future, thanks to some generous funding from the Wellcome Trust and China. I am also very interested in localised intracellular signalling and how it is used by neurons to enforce signal fidelity. Another topic of interest is epigenetic mechanisms of hyperexcitability disorders, such as epilepsy and pain. Generally, ion channels and excitability is still a major theme of our research and I think it will remain important for us within the foreseeable future.
Q6. What made you choose to stay in academia rather than going into industry?
Blue sky research is what fascinates me the most and I think academia is just a more appropriate environment for this.
Q7. Do you feel that pharmaceutical companies do enough to engage with academics and embrace their findings?
Throughout my career I enjoyed some very good relationships and collaborations with industry, yet there is some divide which cannot be ignored. Interestingly, there is a will on both sides to come together for a stronger partnership, yet, due to some inherent differences in goals and processes, this good will often remains unfulfilled.
Q8. How do you feel that the landscape of academia has changed in recent years?
Yes, the landscape is changing, some of it for the better, some of it – not so much so. Among the good trends I would mention emergence of new technologies, drive to have better and larger scale collaboration and cooperation between academic labs, industry, clinics etc. Also increasing internationalization of research is definitely good. What I’m not so happy about is growing bureaucratization, invasion of metrics and short-termism.
Q9. Why do think that ion channels have been a difficult drug target class for the pharmaceutical industry?
This is a big question which would be hard to answer in just a few lines, but there are several reasons to it. One being that since ion channels are membrane proteins, it was difficult to get good crystal structures. Hence, the progress in structural biology of ion channels was relatively slow and this hampered modelling of drug interactions. This is now changing rapidly with the emergence of the Cryo-EM though, so perhaps progress here will enable a new level of SAR-based drug discovery. Another issue is broad expression profiles and high degree of similarity of some important ion channels, which makes it difficult to target them with high selectivity and specificity. A notorious example here is the voltage-gated sodium channels: even though it is pretty clear which subunit to target for pain relief, suitable drugs are still not available.
You can find out more about Nikita’s research activities at his University web page here.