I spoke with Damian about the current state of ion channel industry, automated patch clamp, ion channel antibody development in academia, the new book on methods in patch-clamp electrophysiology, and more. In this interview Damian stumbled into coining the term “painome”, shared his thoughts on how COVID-19 crisis will influence the ion channel field, and rambled on the molecular correlates of consciousness.

I enjoyed the conversation with Damian a lot and I highly recommend reading his interesting thoughts on the significance of ion channels.

Have a good read.

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So, Damian, let’s get to the point right away. Why ion channels? How did you get into ion channels?

Well, that was really quite fortuitous for me. Whilst doing my undergraduate degree, I took a year out from university and worked in industry, so I did, what we call, a ‘sandwich’ year or an industrial placement year at Eli Lilly. And I remember how, at the end of the day of interviews, the Director of Neuroscience at Eli Lilly, David Lodge, said: “OK we’re hoping you would work in the animal behaviour unit. Would you have any problems with that?”. I replied: “I don’t have any problems, but I should mention that I’m allergic to animal fur.” Of course, his immediate reaction was: “Oh, we can’t have you working in the animal behavioural unit, we’ll put you in David Bleakman’s ion channel group”. That’s where I was introduced to ion channels – in David Bleakman’s newly formed ion channel group at Eli Lilly [Erl Wood Manor, UK]. So, I really should’ve been working in animal behaviour but because of my allergy, Eli Lilly put me on to the ion channel track and I’ve been studying ion channels ever since.

So, it appears that you’ve got a passion for ion channels directly from the industry, not academia. I would say it’s rather unusual.

Though I was introduced to ion channels through industry it was really my PhD and postdoctoral work that gave me a passion for ion channels. After I finished my undergraduate studies at the University of Nottingham, I went on the usual academic route by doing a PhD in Annette Dolphin’s lab at UCL and then a postdoc at Columbia University in New York under Steven Siegelbaum. Two world-class ion channel labs and understandably both were huge influences on my early research, and my education and understanding of ion channels.

Well, if you liked your academic route so much, how come that you ended up in industry?

Nearing the end of my postdoc we were witnessing the birth of a revolution in ion channel recording capabilities – various manufacturers were starting to develop automated patch clamp. And that’s what took me from academic ion channel research into industrial drug discovery settings. As my postdoc at Columbia was finishing, I had a great opportunity to become one of the first adopters of automated patch clamp at AstraZeneca in the UK. Divining how this seismic shift would change the landscape of ion channel R&D, I jumped at the chance.

Could you tell me about the life of an electrophysiologist in industry? How different is being an electrophysiologist in industry and in academia? Is it 9 to 5, or you can have long hours like in academia?

In terms of day to day lab work they are both very similar. If your work dictates, for instance if you’re doing time critical tissue-slice work, you’re as likely to have long hours in industry as in academia. In academia you might pop in at the weekend – you wouldn’t necessarily do that so much in industry but you would certainly do analysis maybe at night or weekends if needed.

There’s certainly a number of differences as well. Whereas in academic lab you might be forging new frontiers in the ion channel field, in industry you’ll often be translating or applying this academic groundwork to where it can be best used in terms of drug discovery. Another thing, in industry there is a greater prevalence of the latest technologies and equipment. While a lot of academic labs are still equipped with manual patch clamp rigs, an industrial lab might have those manual patch clamp rigs complemented with more recent automated patch clamp capabilities. Those automated patch clamp platforms mean you have more throughput, but equally means that due to the ‘walk away’ style of automated patch clamp systems you don’t need to be present throughout the experiment, you can turn your attention to other aspects of your research. Another difference is in an industrial lab you tend to work in more cross-technology and cross-expertise science teams. In the industrial setting you can often be working alongside medicinal chemists, DMPK scientists and biophysicists, whereas in academic lab, unless you have that kind of cross-collaboration set up, you’ll probably be doing a lot more of your own specific work within the team that has developed in your lab.

And what about you? Now you’re working at IONTAS. What’s your day-to-day job?

At IONTAS I am the head scientist developing their automated patch clamp capabilities. IONTAS is a world-leading antibody engineering company and have long had an eye on making therapeutic antibodies targeting ion channels, a particularly challenging target class for antibodies. I was brought in to develop and grow their ion channel assay capability. My day-to-day job is essentially ensuring that they have good ion channel assays and that those ion channel assays consistently generate relevant, robust data for the antibody engineers to efficiently develop antibodies along the right therapeutic discovery path. I also spend some of my time visiting other groups, labs, conferences and spreading the word about our KnotBody^TM technology – there is an element of marketing and business development activities in my job.

However, IONTAS is merging with FairJourney Biologics, with the internal KnotBody^TM technology R&D separating to form a new company (Maxion Therapeutics) that’s seeking investment to develop this technology. So, I’m openly seeking new opportunities in the ion channel field. If it involves ion channels, to quote Yosser Hughes ‘I can do that, gis a job’ [ed. a very niche, British cultural reference to Alan Bleasdale’s ‘Boys from the Blackstuff’, a UK TV drama in the 1980s].

That’s good to know. So, as you’ll be looking for a new job, could you tell me what you think about the current state of the ion channel industry? Are there opportunities for ion channel electrophysiologists?

Actually, I’m optimistic and think the ion channel industry is in a very healthy state. Despite a number of large pharma withdrawing significant resources and capabilities from neuroscience, I still feel that it’s in a healthy state because where the big pharma have pulled out, a lot of smaller pharmas and biotechs have sprung up to fill those gaps. And I think that’s good for the field: those smaller companies are driving ion channel research more efficiently. There is a stereotype of big pharmas being like a supertanker: slower and clunkier to turn around, not as efficient and nimble as smaller companies. If the stereotype holds true, from that perspective, I think this is beneficial to the ion channel industry.

Another aspect is we’ve now had nearly two decades of automated patch clamp technology development. And with the vastly improved capabilities and throughput that automated patch clamp has given us, we should soon be reaping the fruits in terms of the greater potential for more fully developed, clinically approved drugs. Consequently, I believe an ion channel blockbuster is imminent. It’s hard to accurately read the runes, but I would say within the next 4-5 years we are going to get one of these big ion channel blockbusters coming to market. And once that hits, the ion channel industry will suddenly be in the spotlight: I think a lot of big pharma ion channel programs will either be resurrected or they’ll be starting entirely new programs; once you get one ion channel blockbuster to market the ion channel field will really explode on the back of it.

I genuinely think that in the next few years we will see an ion channel blockbuster drug leading to a Renaissance in ion channel R&D.

DAMIAN BELL

Perhaps I’m being overly optimistic. But as we get increased global adoption of automated patch clamp capabilities, this will funnel into increased development and building of significant ion channel programs whether that be in academia or industry. It may be a little naïve, but I genuinely think that in the next few years we will see an ion channel blockbuster drug leading to a Renaissance in ion channel R&D.

Wow, that’s so optimistic. I really hope your predictions come true. But with such a development of automated patch clamp is there any threat of unemployment for ion channel electrophysiologists? Will automated patch clamp robots replace electrophysiologists in the end?

Good point. This is a typical concern, in any industry, as things become automated. But I still think you need the expertise to fully understand and analyze the data you get from an automated patch clamp platform and, of course, even if you can run a well-defined assay you still need someone who will design, develop and build those assays in the first place. Automation certainly takes you a long way down the road in terms of increasing the number of ion channels and drugs you can test on those ion channels. But you still need expert eyes and minds really looking at the data in detail and designing protocols for automated patch clamp. And, even the best automated patch clamp machines still cannot necessarily do everything you can do on a manual patch rig. A lot of companies, even though they might have several automated patch clamp platforms still often have at least a manual rig or two to do some deeper dive experimentation. For example, having done your huge compound library screen, filtering it down to your top five compounds you would then probably do some really detailed analysis and in-depth investigation on those five compounds in terms of mechanism of action, where and how they’re acting on your ion channel of choice, and you would do most of that primarily by manual patch clamp. So, I don’t think that the development of automated patch clamp is necessarily going to be the death knell for ion channel electrophysiologists, I think there’s always going to be a need for their expertise. Despite automated patch clamp potentially taking over the manual capabilities there is still a need for good electrophysiologists, there is still need for their input and creativity in terms of how you apply certain tests, how you design them, how you run them most efficiently on the automated patch clamp platforms and, as I said, manual patch still has a very important and useful role in any good ion channel lab.

OK. And one more question about automated patch. In your LinkedIn profile you’ve mentioned that you worked with different automated patch clamp platforms. What’s the difference between those platforms? Do you have a preferred one?

I personally have a preference for the QPatch from Sophion. However, that’s based on my own career trajectory: I started off on a QPatch and I’m still working with a QPatch; it’s a very good machine. But over my 16 years of automated patch clamp use I’ve worked with several other platforms from different manufacturers and they all have their uses in different circumstances, in different R&D programs. Some platforms might be more flexible, some might have higher throughput, but no one platform is perfect. They all have advantages and disadvantages. Personally, I would say that Nanion and Sophion are neck and neck in terms of their capabilities in making and developing automated patch clamp systems; both make very good machines. I also think that competition between those two main players – and other APC specialists – is very healthy, constantly pushing and developing the capabilities and advancing the field.

As you are working at an antibody engineering company, could you tell me what the main players in ion channel antibody engineering business are?

Over the years, there have been numerous companies that have looked at ion channel antibodies but I would highlight three companies with the most compelling and innovative programs: IONTAS (take with a pinch of bias), TetraGenetics and Ablynx.

At IONTAS we’ve developed the KnotBody^TM technology where we fuse a venomous species knottin toxin into an antibody background. Essentially, we combine the ion channel modulating capability of a knottin with the therapeutic functionality of an antibody. This KnotBody^TM format has numerous benefits over existing formats and it won’t be long before this will be one of the key technologies for generating ion channel specific antibodies [ed. this technology will now be developed by Maxion Therapeutics, a spin-out company from IONTAS].

TetraGenetics’ R&D scientists are doing some great work: in Tetrahymena they have a very robust expression system giving them the capability to express ion channels at high quantities and quality, allowing them to develop antibodies against this antigenic ion channel material.

Ablynx has been making some nice molecules, taking advantage of the modular building blocks of antibodies: the heavy & light chains, the CDRs (the complementarity determining regions), etc. Using the modular ‘business end’ sequences of an antibody they’ve managed to ‘shrink’ an antibody down to its minimal functional binding components – dubbed a Nanobody. They have some interesting ion channel Nanobodies.

As for big pharma – for instance J&J, Amgen, Genentech, MedImmune/AstraZeneca – they’ve all had some great programs, but many of them were either shelved or binned. And I haven’t seen much data coming out those labs for quite a while now. Of course, it’s hard to know where they are now in terms of ion channel antibody development, they tend to keep their cards close to their chest for the obvious IP related reasons.

And what about ion channel antibody engineering in academia? You know that various labs in academia try to develop their own ion channel antibodies. What are your thoughts on quality and future of those antibodies?

A number of academic labs over the last decade or two have made very good ion channel antibodies. However, there have also been some well documented problems with academic ion channel antibodies – when industrial labs tried to replicate those antibodies they haven’t worked. I’m not quite sure why that is. For instance, there was a very interesting and intriguing Nav1.7 antibody that came out of Duke University several years ago, however both Genentech and Amgen couldn’t get it to work the way that the academic group at Duke had. (ed. the paper from Duke University has been retracted on 25.06.2020. See the retraction notice here.). I think more and more researchers will be turning to antibodies targeting ion channels, but it’s clearly a very challenging target class. Many researchers have been trying, but they haven’t created a particularly good modulating ion channel antibody as yet. Leaving aside the Duke story, there are some good ligand-gated ion channel antibodies but for the voltage-gated ion channels it’s a different story: they’ve been very difficult to make good, modulating antibodies against. The problem is that though you can make a good, binding antibody to a voltage-gated ion channel, it might not necessarily modulate the ion channel. And that’s where a significant hurdle comes in – how to make good, modulating ion channel antibodies? One problem is a very limited number of externally facing epitopes that voltage gated ion channels have, compounded by the fact that those limited epitopes are often highly fluid and mobile and could be changing rapidly over the gating cycle of an ion channel – one epitope may only be available for a few milliseconds every minute or two.

All of these issues make ion channels a difficult target class for antibody drug discovery. Nonetheless, as we improve our capabilities to express purified, stable, functional ion channel protein in a membrane-like environment, we can potentially develop antibodies to those short-lived, external epitopes that might give rise to better binding and, critically, modulating ion channel antibodies.

So, what is the best strategy for scientists in academia planning to produce therapeutic ion channel antibodies?

I wouldn’t do it yourself, don’t try this at home kids; I would suggest collaborating with an ion channel antibody engineering company. Joking aside, of course it’s possible to do it yourself and there are some excellent academic labs that have ion channel antibody development programs. However, there are a number of areas where an industrial collaborator could significantly contribute to an academic therapeutic antibody development program, and it’s not just a case of finding good, modulatory antibodies. Obviously, this is a big challenge in its own right, but then beyond that there is a question of the developability of your antibody. You might find a great antibody but how do you then produce sufficient quantities of that antibody? How do those antibodies behave in terms of solubility or how they aggregate – or hopefully don’t aggregate – at high concentrations? All of these traits can be very difficult to build into your therapeutic antibody discovery program and experts from industry can help in developing your antibodies, improving them to be therapeutically viable.

If you were to start a company in the ion channel field what would it be?

This question has certainly crossed my mind a few times over the last few years. My focus is routinely in the lab and on my team, my thinking’s not usually on the building-a-business side of things, and yet I do see obvious areas and gaps where I think there could be some great ion channel research and drug development. Much of my background has been in chronic pain. And I still believe ion channels are going to be key in chronic pain therapies. There has been a lot of research going into it and yet we are still to get that true chronic pain ion channel drug. So, if I was to start a new ion channel company it would probably be in the chronic pain field. It would likely involve Nav1.7, but also other ion channels like Nav1.8, Nav1.9, HCN2, TRPA1 and TRPV1. However, it might not necessarily just be the ion channels themselves, it would also be the upstream/downstream proteins and pathways around the ion channels. It’s also becoming clear that like cancer before it, chronic pain is a vast umbrella term covering over a hundred pain states, diseases and pathologies, so future chronic pain medications are going to be increasingly tailored and personalized to a few pain patient cohorts. There won’t be a single magic bullet to solve chronic pain but dozens, potentially even mixed and matched, to a specific patient’s ‘painome’ – not sure that’s even a term, think I might’ve just coined a whole new field of medicine. Finally, considering my experience with IONTAS, my new company would most probably involve antibody drug discovery. I would be looking to use these larger, in vivo longer lasting molecules with the multi-specificity and multi-functionality that you can build into an antibody as opposed to the narrow chemical confines of a small molecule.

What’s your opinion on COVID-19 crisis? Will it influence ion channel research and business?

As for any lab-based work, the way we do ion channel research is going to be changed substantially. Our work style will become more flexible. It should become more environmentally friendly because you won’t be doing as much commuting and traveling for work or for various meetings, with more virtual meetings and conferences. Overall, I think a lot of people will be reevaluating the way they do things and changing their lifestyle and their work capabilities accordingly.

Another point is with COVID-19 enveloping us all across the world, the attention of many people, me included, has switched to: “How can I help? What can I do?”. And, since my expertise is in ion channels, I started thinking in terms of where ion channels might have an impact. For instance, there are ion channels highly specific to viruses. And considering that viruses only carry the bare minimum of what they need to replicate, then these ion channels must be critical in their replication cycle. Consequently, viral ion channels will become targets for antiviral drug development. Another key aspect is that ion channels are involved in the immune inflammatory response, and so ion channels will have a key role in the response of an organism to infection by pathogenic viruses. Antivirals are clearly going to be increasingly important now and in the future pandemics: ion channels are likely to be targets for antivirals, which will stimulate ion channel R&D.

From your LinkedIn posts I learned that apparently there is a new book on ion channels to be published very soon. What will be that book about?

Together with Mark Dallas [University of Reading] we have been asked to edit a book, compiling different chapters on methods in patch clamp electrophysiology. The book has a really broad scope and aims to be a guide to methods for novice and expert alike: we obviously cover manual patch clamp through to automated patch clamp, and onto more recent advances in techniques and applications like optogenetics. We’ve brought together experts across the world to each write a chapter on their specific technique, their specific area of expertise in the field of patch clamp methods. So, yes, that book will be published by Springer Nature in August this year – we’re looking forward to that coming out and hope it will be a useful, practical resource for any lab wanting to make ion channel recordings.

In one of your profiles in the internet I read that you are “passionate about ion channels, bordering on an obsession”. Could you comment on this?

Yep: I’m a bit of an ion channel obsessive. Ion channels are so critical, they control so much of our physiology, so much of what makes us ‘us’. And this goes from sensory perception to how those perceptions are collated and processed, how your brain determines and defines what those sensory perceptions are telling you.

If you really want to get deep you could even argue that ion channels are the molecular source of the soul.

DAMIAN BELL

We can’t think without ion channels. And so, if you can’t think then how can you have consciousness? Consciousness is the kernel of our humanity. If you really want to get deep you could even argue that ion channels are the molecular source of the soul. Well, maybe that is a little too deep, but think about it: literally everything we do, and see and feel, how we perceive everything – it’s all driven through ion channels. Even my memories – like the memory as a four year old helping my dad in the garden, putting the garden fork clean through my sandal, grazing the skin between big and second toe – all come through ion channels.

Maybe I’m stretching it too much but our entire perception of the world, including our previous perceptions and our histories, they all come through ion channels. For instance, some of the strongest, most visceral memories you can have are tied to smells, like Proust’s proverbial madeleines. You can have a smell twenty years ago, twenty years later when you have that same smell it transports you to that original smell, to that location, to everything that you perceived at that point in time – it’s incredible, fantastical even.

I have ion channels, therefore I think, therefore I am.

DAMIAN BELL

Obviously, there is a lot more going on than simply ion channels. Nonetheless, ion channels are key elements in your perception of the world, in your personal history within the world. And it’s not just about the sensory perception, it’s also about how you perceive yourself, how you perceive others, your place in the world past, present and future. To mangle Descartes’ beautifully pithy dictum: I have ion channels, therefore I think, therefore I am. In other words, ion channels really put the ‘I’ into consciousness … sorry, like Icarus my flight of fancy went too far.

That’s a very interesting perspective. Thank you for sharing it. Well, my last question will be about your plans for the future. You said that you’re open for new opportunities. What kind of opportunities are you looking for?

Well, unsurprisingly, if it’s an ion channel related project, I’m always open to working with great scientists towards great collective science. If I think it’s an exciting, innovative path to take in ion channel drug discovery, or even academic ion channel research, then I’d love to be involved.

Even academic?

Yes, I think you can quite readily go into industry, get a good training in industry and take your techniques, knowledge and expertise into academia. It works both ways: there are great scientists in industry and great scientists in academia and I think they can both help each other immensely either through collaborations or by going back and forth between industry and academia, taking the best practices and insights learnt along the way. I’ve long been advocating for having automated patch clamp systems in academic labs and I’d love to set up, for instance, a core-facility used by several academic labs or by an institution to really drive ion channel academic research in such a shared, collaborative environment.

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I’m thankful to Dr. Damian Bell for taking the time to talk with me and sharing his interesting insights.

If you have questions to Dr. Bell, you can contact him via LinkedIn or Twitter.

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Images by Damian Bell