Introducing Damian Bell: as a new member of the team at Metrion we are using an abridged version of an interview by Artem Kondratskyi for ionchannellibrary.com. A big thank you to Artem for sharing this interview and a quick plug for his website – we highly recommend it as an excellent resource for anyone interested in ion channels.
Artem spoke with Damian about his career, the current state of ion channel industry, automated patch clamp, ion channel antibody development, the new book on methods in patch-clamp electrophysiology, and more.
Whilst doing my undergraduate degree, I did an industrial placement year at Eli Lilly [Erl Wood Manor, UK]. I was initially pencilled in to work in the animal behaviour unit. However, I’m allergic to animal fur. Lilly had recently hired David Bleakman to set up an ion channel group. So, serendipitously my allergy took me into the world of ion channels.
Though Lilly and David Bleakman provided the initial spark (pun intended), it was really my PhD and postdoctoral work that fuelled my fire 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, two brilliant scientists that understandably were huge influences on my early research and understanding of ion channels.
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 and D, I jumped at the chance.
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, biotechs (including virtual drug discovery programmes) and CRO’s have sprung up to fill those gaps. And I think that’s good for the field: those smaller, more diverse range of companies are driving ion channel research in more efficient and innovative directions.
Smaller, more diverse companies are driving ion channel research in more efficient and innovative directions.
Damian Bell, Senior Scientist, Metrion Biosciences
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. As with any predictions, it’s hard to accurately read the runes, but I’d say within the next two to three years we are going to get one of these big ion channel blockbusters coming to market. And once that hits, the ion channel R&D 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.
Of course, this is a typical concern, in any industry, as things become automated. But I still think you need the expertise to fully understand and analyse 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. 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; manual patch still has a very important and useful role in any good ion channel lab.
I personally have a preference for the QPatch from Sophion. However, that’s based on my own career path: 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 and D programmes. 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 like Fluxion – is very healthy, constantly pushing and developing the capabilities and advancing the field.
Over the years, there have been numerous companies that have looked at ion channel antibodies but highlighting the three companies with the most compelling and innovative programs: IONTAS (take with a pinch of bias), Tetragenetics and Ablynx.
At IONTAS we developed the KnotBodyTM 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 KnotBodyTM 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.
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 have been making some nice molecules, taking advantage of the modular building blocks of antibodies: the heavy and 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 programmes, 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.
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. since the interview this publication has been retracted – https://www.cell.com/cell/fulltext/S0092-8674(20)30751-0?dgcid=raven_jbs_etoc]. 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, bindingantibody 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.
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 personalised to highly selected and defined 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.
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 travelling for work or for various meetings, with more virtual meetings and conferences. Overall, I think a lot of people will be re-evaluating 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.
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.
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.
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.
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.
Introducing Damian Bell: as a new member of the team at Metrion we are using an abridged version of an interview by Artem Kondratskyi for ionchannellibrary.com. A big thank you to Artem for sharing this interview and a quick plug for his website – we highly recommend it as an excellent resource for anyone interested in ion channels.
Artem spoke with Damian about his career, the current state of ion channel industry, automated patch clamp, ion channel antibody development, the new book on methods in patch-clamp electrophysiology, and more.
Whilst doing my undergraduate degree, I did an industrial placement year at Eli Lilly [Erl Wood Manor, UK]. I was initially pencilled in to work in the animal behaviour unit. However, I’m allergic to animal fur. Lilly had recently hired David Bleakman to set up an ion channel group. So, serendipitously my allergy took me into the world of ion channels.
Though Lilly and David Bleakman provided the initial spark (pun intended), it was really my PhD and postdoctoral work that fuelled my fire 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, two brilliant scientists that understandably were huge influences on my early research and understanding of ion channels.
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 and D, I jumped at the chance.
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, biotechs (including virtual drug discovery programmes) and CRO’s have sprung up to fill those gaps. And I think that’s good for the field: those smaller, more diverse range of companies are driving ion channel research in more efficient and innovative directions.
Smaller, more diverse companies are driving ion channel research in more efficient and innovative directions.
Damian Bell, Senior Scientist, Metrion Biosciences
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. As with any predictions, it’s hard to accurately read the runes, but I’d say within the next two to three years we are going to get one of these big ion channel blockbusters coming to market. And once that hits, the ion channel R&D 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.
Of course, this is a typical concern, in any industry, as things become automated. But I still think you need the expertise to fully understand and analyse 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. 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; manual patch still has a very important and useful role in any good ion channel lab.
I personally have a preference for the QPatch from Sophion. However, that’s based on my own career path: 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 and D programmes. 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 like Fluxion – is very healthy, constantly pushing and developing the capabilities and advancing the field.
Over the years, there have been numerous companies that have looked at ion channel antibodies but highlighting the three companies with the most compelling and innovative programs: IONTAS (take with a pinch of bias), Tetragenetics and Ablynx.
At IONTAS we developed the KnotBodyTM 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 KnotBodyTM 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.
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 have been making some nice molecules, taking advantage of the modular building blocks of antibodies: the heavy and 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 programmes, 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.
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. since the interview this publication has been retracted – https://www.cell.com/cell/fulltext/S0092-8674(20)30751-0?dgcid=raven_jbs_etoc]. 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, bindingantibody 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.
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 personalised to highly selected and defined 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.
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 travelling for work or for various meetings, with more virtual meetings and conferences. Overall, I think a lot of people will be re-evaluating 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.
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.
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.
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.
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.
Introducing Damian Bell: as a new member of the team at Metrion we are using an abridged version of an interview by Artem Kondratskyi for ionchannellibrary.com. A big thank you to Artem for sharing this interview and a quick plug for his website – we highly recommend it as an excellent resource for anyone interested in ion channels.
Artem spoke with Damian about his career, the current state of ion channel industry, automated patch clamp, ion channel antibody development, the new book on methods in patch-clamp electrophysiology, and more.
Whilst doing my undergraduate degree, I did an industrial placement year at Eli Lilly [Erl Wood Manor, UK]. I was initially pencilled in to work in the animal behaviour unit. However, I’m allergic to animal fur. Lilly had recently hired David Bleakman to set up an ion channel group. So, serendipitously my allergy took me into the world of ion channels.
Though Lilly and David Bleakman provided the initial spark (pun intended), it was really my PhD and postdoctoral work that fuelled my fire 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, two brilliant scientists that understandably were huge influences on my early research and understanding of ion channels.
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 and D, I jumped at the chance.
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, biotechs (including virtual drug discovery programmes) and CRO’s have sprung up to fill those gaps. And I think that’s good for the field: those smaller, more diverse range of companies are driving ion channel research in more efficient and innovative directions.
Smaller, more diverse companies are driving ion channel research in more efficient and innovative directions.
Damian Bell, Senior Scientist, Metrion Biosciences
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. As with any predictions, it’s hard to accurately read the runes, but I’d say within the next two to three years we are going to get one of these big ion channel blockbusters coming to market. And once that hits, the ion channel R&D 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.
Of course, this is a typical concern, in any industry, as things become automated. But I still think you need the expertise to fully understand and analyse 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. 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; manual patch still has a very important and useful role in any good ion channel lab.
I personally have a preference for the QPatch from Sophion. However, that’s based on my own career path: 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 and D programmes. 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 like Fluxion – is very healthy, constantly pushing and developing the capabilities and advancing the field.
Over the years, there have been numerous companies that have looked at ion channel antibodies but highlighting the three companies with the most compelling and innovative programs: IONTAS (take with a pinch of bias), Tetragenetics and Ablynx.
At IONTAS we developed the KnotBodyTM 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 KnotBodyTM 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.
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 have been making some nice molecules, taking advantage of the modular building blocks of antibodies: the heavy and 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 programmes, 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.
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. since the interview this publication has been retracted – https://www.cell.com/cell/fulltext/S0092-8674(20)30751-0?dgcid=raven_jbs_etoc]. 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, bindingantibody 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.
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 personalised to highly selected and defined 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.
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 travelling for work or for various meetings, with more virtual meetings and conferences. Overall, I think a lot of people will be re-evaluating 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.
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.
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.
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.
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.