Marc has spent the past three decades researching ion channels within both academia and industry environments. Here, he shares some intriguing insights into this promising field of drug discovery.
Q: What’s motivated you to focus your entire career on ion channel research?
A: It all started when I was an undergraduate in New Zealand doing my physiology degree. I attended a lecture on neuronal excitability and performed some hands-on animal experiments (back in the day before the 3Rs came into effect). From that point, the light bulb in my brain went on and has stayed on for the past 35 years!
I’ve worked all over the world (Australia, New Zealand, the US and now the UK) but my motivation has largely remained unchanged. I’m fundamentally driven by science, as well as my fascination with how ion channels work and what effects they have on cell function. As I’ve spent the last 15 years in industry, my work is now more applied than theoretical, but my whole career has focused on studying a range of ion channels and their role in human disease.
Q: Can you explain why ion channels are important to study for drug discovery?
A: Ion channels facilitate the flow of ions such as sodium, potassium and calcium across cell membranes and are a site of action for neurotransmitters like GABA (gamma-aminobutyric acid). This function underpins crucial processes in a vast array of human cells, tissues, and organs, ranging from nerves in the brain and the peripheral nervous system to hormone-secreting cells in endocrine glands. As they play such a key role in so many physiological processes, ion channels have long been validated prime targets for drug discovery.
In fact, ion channel pharmaceuticals are already a successful drug class. One example is Lyrica (or Pregabalin), which was ranked as high as #17 in the top 200 drugs by US retail sales in 2018. However, there’s still an ongoing challenge to design and develop more potent and selective therapies with fewer side-effects and greater clinical efficacy.
Q: What challenges are being overcome in the search for novel ion channel targets?
A: We’re now able to better identify and validate both existing and new ion channel genes in human disease. This is thanks to the huge databases of patient blood, tissue samples and DNA sequences coupled with long-term demographic and epidemiological data.
Excitingly, we’re already seeing scientists advancing research using this data. If we look at rare diseases, for example, the genotyping of patients is linking genetic mutations with abnormal ion channel function, such as Nav (voltage-gated sodium channels) in erythromelalgia and small fibre neuropathy. Furthermore, in common diseases, SNP (single nucleotide polymorphisms) profiling and GWAS (Genome Wide Association Studies) of large patient databases and epidemiological cohorts are revealing the involvement of a broad range of ion channel genes. One notable example is the use of GWAS to confirm a likely contribution of the TRPM8 ligand-gated ion channel to migraine, which should boost the subsequent development of TRPM8 antagonists to treat chronic pain and migraine.
However, in this pharmacogenomics era, we still face significant challenges in target validation. Although GWAS is a valuable technique, it can only tell you if a genetic variant is associated with a specific trait—it doesn’t reveal the underlying cause. Genetic hits therefore need to be robustly replicated and then functionally validated before committing huge resources to using them in major drug discovery efforts.
Q: What underpins the successful discovery of ion channel ligands and modulators?
A: The design of more useful and effective ion channel ligands and modulators has emerged through structure-based drug design, which combines two recent advances. First, the development of more specific and selective pharmacology (e.g. small molecules, toxins, antibodies) and second, the elucidation of ion channel protein structures through cryogenic electron microscopy (cryo-EM) techniques. With more potent and selective ligands, we can more reliably validate the role of specific ion channels in disease through functional assays and animal models.
Q: Can you describe some recent advances in targeting ion channels to treat disease?
A: Disease modelling is a burgeoning area, driven by developments in 2D and 3D human stem cell-derived cultures and CRISPR gene editing. Validated translational assays, such as iPSC (induced pluripotent stem cell) cardiac or neuronal models of an ion channel disease phenotype, can be used to screen for drugs to more effectively treat both common and rare diseases, even on a personalised patient-by-patient basis.
There’s also a growing push to develop biologics that modulate ion channels, which promises greater selectivity and potency, coupled with lower costs of production. One example is the fine-tuning of animal toxins that can target various domains of ion channels. Some of these have made it into the clinic, such as the cone snail toxin Ziconotide for pain. However, administering peptides cost-effectively and easily to patients remains a challenge.
Q: What’s next for ion channel screening and research?
A: My first choice for the ‘next big thing’ is the advancement in cryo-EM techniques and computer modelling. These techniques facilitate the faster generation of high-resolution images of native human ion channel proteins from every major voltage- and ligand-gated family. In fact, the images obtained are already yielding novel chemical ligands and facilitating structure-based drug design.
My second choice is optogenetics, enabled by the development and optimisation of genetically encoded channels and voltage sensors (such as channelrhodopsin and GCaMP) in academia that is now delivering ion channel screening reagents to the drug discovery world. Essentially, optogenetics allows the sophisticated control and measurement of cell membrane potential, excitability and functional outputs in a scalable fashion in native cells. The cells are in a more physiologically relevant state compared to, say, dissociated heterologous cells on an automated patch clamp platform, allowing us to gain insights that are more translatable to the in vivo environment.
I strongly believe that optogenetics could facilitate phenotypic screening with high throughput and high content, but lower cost than traditional techniques. It should also be amenable to study both native rodent tissue and human stem-cell-derived cultures – I imagine that such use could occur both at the top of a screening cascade (for phenotypic screening and target validation), as well as part of mechanistic studies for lead compounds as they move towards the bottom of the drug discovery process..
Q: Do you have any advice for students and early career researchers?
A: It’s essential to find something you’re passionate about and use that drive, as well as mentors and organisational resources, to figure out a career path that allows you to pursue your interests. Ultimately, the onus is on you to do your due diligence and seek out as much advice as you can—and make sure you have a ‘plan B’ to turn to if all else fails!
I’d also encourage students to take advantage of industrial placements and pharma-sponsored postgraduate degrees available here in the UK. Experiencing an alternative R&D environment outside academia is very smart and useful, as it can widen your training and teach you how to ‘do’ science in a way that books and classes can’t.
Q: Do you think attending events like ELRIG’s Drug Discovery 2019 conference can benefit drug discovery scientists?
A: I feel that focused and multi-disciplinary conferences like ELRIG’s Drug Discovery 2019 conference are crucial to disseminating and promoting the enthusiasm and excellence we have for science. It is vital to have a good mix of academic insight and commercial applications.
Additionally, given the uncertainty over Brexit and possible impacts on scientific and commercial links with Europe, I believe it is important to support local experts, laboratories and companies that are part of the thriving R&D sector in the UK. I think events and networks such as the ELRIG Drug Discovery conference are key to making sure that happens.