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I had a great conversation with Andrea Brüggemann about her career, the role of a CSO, fundraising, advantages and limitations of the automated patch clamp (APC), APC trends and more. I learned a lot from Andrea and I highly recommend reading this interview to everyone interested in ion channels and automated patch clamp.

Have a good read.

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Andrea, just before we start, I’d like to ask you how we should pronounce “Nanion” and what it means.

Nanion is merged from the words “nano” and “ion”. In fact, Nanion was founded as a spinoff of the Center for Nanoscience within the Ludwig Maximilian University in Munich, so that’s where the “nano” comes in. As Nanion is a German company, when we speak German we say [na-nɪ-on] but when we speak English we often say [næ-na-ɪən] because people are used to saying it like this. But, you know, it doesn’t really matter for us how you pronounce it. What’s important is how our instruments can help people in their research and drug development.

OK. So, now, let’s start with your backstory. How did you become interested in ion channels?

Well, while studying physics in Bochum I was sort of looking left and right to complement my physics studies with physical-chemistry or biochemistry. The biochemistry lectures that I attended were given by Prof. Olaf Pongs – a great lecturer and one of the first scientists cloning the Shaker channel from Drosophila (see here). Olaf was looking for an electrophysiologist and since he found out that I’m a physicist sitting in his biochemistry lectures, which was rather odd, he was thinking that this would be perfect if I could do my diploma thesis with him in electrophysiology and ion channels. At that time I didn’t even know what ion channels were and what electrophysiology was, but my curiosity sort of said “yes” for me and so I ended up doing my Master’s thesis on potassium channels with Olaf Pongs.

Jeffrey Warmke had just published the sequence of Drosophila ether-a-go-go (Deag), but not yet its function (see here). As a kind of practical course in molecular biology, I re-cloned eag from Drosophila. Then the idea was to see how it regulates Shaker, because at that time eag was thought to be a regulatory subunit, not a channel itself. So I injected Shaker RNA as a positive control, eag and Shaker as a test condition and eag alone as a negative control into Xenopus laevis oocytes. And to our big surprise the negative control in oocytes had 50 micro Ampere current, indicating that eag gene encodes a functional ion channel on its own.

So, you were a physicist who learned a bit of molecular biology and cloned an ion channel.

Yes, I know it’s rather unusual, but I guess I never take the straight path. I think it’s because of my insatiable curiosity. Even though it might not be the usual thing for a physicist to clone an ion channel, I am happy that I learned the basics of molecular biology. Later on, to analyze the function of the cloned eag gene Olaf Pongs sent me to Göttingen to learn electrophysiology. He sent me to the group of Walter Stühmer, who was part of Erwin Neher’s group at the Max Planck Institute for Biophysical Chemistry. I was very lucky to be sent to the center of electrophysiology.

I liked it there so much that I also stayed in Göttingen for my PhD, this time at the Max Planck Institute for Experimental Medicine with Walter Stühmer and Luis Pardo. It was a fantastic time and I am very thankful that I was allowed to learn so much from the great electrophysiologists in Göttingen.

The next step in my career took me to the Pharma Company Hoechst Marion Roussel (HMR) in Frankfurt, which is now Sanofi-Aventis.

And what did you do at Sanofi-Aventis?

I was a part of the cardio-vascular research department where we had two electrophysiological labs: one working on native tissues like cardiomyocytes (managed by Heinz Gögelein) and another one (my lab) studying ion channels overexpressed in oocytes, HEK or CHO cells. We were always comparing native tissues to overexpressing systems and all pharmacological measurements were done with manual oocyte and patch clamp setups.

The typical ion channel targets in cardio-vascular field at that time were, for example, Kv1.5, Kv4.3, BK, HCN, KvLQT1 and GIRK. And at some point we kind of started doing some ion channel testing and assay development for other departments inside the company, and that led to the creation of an ion channel platform at Sanofi-Aventis, which I was appointed to manage. The nice thing for me in that position was that I came to know about all ion channel projects which were running at Sanofi-Aventis.

So, you were the head of the platform and a lab leader at a big pharma company. Many people would dream of this position, but you decided to move to a small company. What went wrong at Sanofi-Aventis?

No, nothing went wrong. Everything was perfect. In fact, as we measured everything with oocytes and manual patch clamp, and this being the bottle neck in ion channel drug development, I was looking for automated patch clamp technologies. And so, I contacted the companies developing automated ion channel screening technologies at that time. There were CeNes in the UK (which later spun out Xention, then Metrion), Flyion in Germany, Cytion in Switzerland and Axon Instruments in the US. I visited those companies, to see the status of their technologies. Remember, we are now talking about 2000 and none of them really had an instrument. So, after all discussions with these different groups, Cytion said they needed a person with a deep knowledge of ion channels combined with a good understanding of what pharma companies need. And they made me an offer that I couldn’t refuse. Both the financial conditions and the possibility to live in the beautiful city of Lausanne were very attractive. So, I moved to Switzerland.

OK, I got it. You’ve quit a good job for a dream job. But why did you move to Nanion later on? Both Cytion and Nanion were developing planar automated patch clamp technology. What was your motivation back then?

Well, I didn’t really have a choice. Cytion was bought by Molecular Devices and, shortly after that decision, they closed Cytion. And while that was happening, I had already looked for alternatives and the players at that time were Flyion, Cytocentrics, Axon, Sophion and Nanion. In the end, I decided to go with Nanion. I had met Niels and Michael, we got along really well, Munich is a great city to live in and for me, as a manual patch clamper, Nanion’s borosilicate glass substrate was the way to go.

Sanofi-Aventis, Cytion, Nanion. What about IonGate Biosciences?

Oh, that was an interesting project and a valuable experience from which I’ve learned a lot. In the late 90s quite a number of drugs have been withdrawn from the market because of cardiac side effects. Therefore the FDA came up with new guidelines recommending that all drugs have to be evaluated for their effect on hERG. And I guess over some beers with friends and colleagues of mine, including Bela Kelety, we thought this FDA regulation should create a big need of hERG tests. The idea of founding IonGate Biosciences was born. Thiemo Gropp and Bela Kelety had a close contact to Ernst Bamberg and Klaus Fendler at the Max Planck Institute (MPI) for Biophysics in Frankfurt. So, IonGate was able to use some space for the hERG measurements at the MPI and worked on the automation of the transporter measurement technology (solid supported membranes (SSM) technology) developed in the lab of Ernst Bamberg. It was later commercialized under the name SURFE²R (SURFace Electrogenic Event Reader) (see here).

That was fun, but when I’ve quit Sanofi-Aventis and moved to Cytion the investors were thinking that Cytion is too much of a competitor to IonGate and so they asked if I could sell my shares. At that moment I was really disappointed about this but finally I decided to sell my shares and … some years later IonGate went bankrupt. I was already at Nanion at that time when IonGate investors asked if Nanion would want to buy what was left over from IonGate. Nanion bought the IonGate’s remnants and now the SURFE²R technology is further developed and sold by Nanion. So, IonGate sort of came back to me.

So, you kind of founded a company in a garage. But where did you find the patch clamp rigs to do the hERG tests on?

We bought them. Actually, we’ve easily found investors for IonGate, and from the very beginning we had enough money to buy everything we needed for our company. That was our advantage, but at the same time also IonGate’s biggest problem – a lot of venture capital. You know that venture capital funds always invest with an exit in mind. The problem of IonGate was that we could make a living by doing the hERG tests and developing the SURFE²R technology, but it was very difficult to find an exit strategy. I would say, this is what killed IonGate – the exit of the investors.

Think well about how much money you really need from investors. Don’t take more money than you need.

ANDREA BRÜGGEMANN

At Nanion we didn’t make the same mistake. We got a very small investment at the beginning and after 7 years we were able to do a management buyout. So, now Nanion is mainly owned by Niels, Michael and me. That makes us independent of any investors and allows us to make long-term decisions. As a recommendation I would say, think well about how much money you really need from investors. Don’t take more money than you need, because at some point the investor needs an exit and it is more difficult if a lot of money was invested into the company.

Totally agree. I think Nanion here could serve as an exemplar for anybody planning to start their own company. So many startups now just embrace the fundraising culture and become addicted to it which could be a bad strategy in the long run.

Yes, but I have to say that in Munich we have sort of an ecosystem or a community of startups and companies that help each other and, let’s say, share more or less the same point of view on fundraising. For example, there are a lot of spinoffs from the Center for NanoScience in Munich, such as NanoTemper, attocube, ibidi, and they are all very successful and they all started small by using their proper funds and minimal initial financing from the outside. Some of them did take later investments to further develop their businesses but initially they limited their seed investments to an absolute minimum. So, in this aspect, all these companies are very similar to Nanion. And I think that this is so, at least in part, because there is a strong connection between these companies in Munich and every year the BioM investor organizes a Christmas dinner for all these entrepreneurs, startup companies, small biotech and also pharma companies to interact, share their ideas and visions, and support each other.

That’s great. So, now you are the Chief Scientific Officer (CSO) at Nanion. What does it mean? What is it like to be a CSO?

At the beginning, the CSO was the person who did everything, from exchanging a light bulb to developing high-end technology.

ANDREA BRÜGGEMANN

Well, my job has totally evolved. At the beginning, the CSO was the person who did everything, from exchanging a light bulb to developing high-end technology. I tried to transform everything that I had learned from conventional patch clamp into the planar world and put my experience into words so that Michael George, our CTO, could then put it into the software and Niels Fertig, the CEO, could do device/consumable improvements. Initially, it was a lot of work on, for example, what solutions to use, how to harvest the cells, how much suction to apply, which holding potential to use, etc. We tested a lot of different cell types and ion channels until we got a functional device.

Later, I was mainly testing our devices, first the Port-a-Patch, then the Patchliner, and finally the SyncroPatch, telling the developers what I think should be improved. So, I’ve never written the software and never built a device, I was testing and reporting my experience. With the company growing we had more and more electrophysiologists with great expertise joining us, and so I started working less with the instruments. My job has therefore changed and I am spending my time at conferences or at customers trying to understand where the field is going and giving this as a feedback to the company. One week I am at the NIH, another week in Janelia, today I’m in Chile teaching a course with Ramon Latorre and tomorrow I’m in Chicago working on a new approach with Pancho Bezanilla.

I’m also trying to understand which new functionalities we can introduce into our instruments and I test different ideas and do proof-of-concepts with experts around the world. Then I bring these ideas and concepts to Nanion where we have a great team that can make great products out of them. So, this is what I do now.

So, you visit many conferences and meet a lot of people working in the ion channel field now. One can get the impression that you know everyone in the field and everybody knows you. Could you tell me about the current state of the ion channel industry?

That’s an interesting question. Back in the 2000s ion channel drug development was a major field at pharma companies. Ion channel drugs were among the top drug targets for such disorders as atrial fibrillation or diabetes, for example. However, at some point most of these ion channel R&D programs sort of petered out and so there was a dip in this field for quite a while. But now we see that CFTR drugs are being approved by the FDA. For example, Vertex and Enterprise Therapeutics have strong CFTR programs. There are some interesting programs on other channels, such as TMEM16A, ENAC as well as NMDA and GABA receptors. In 2019 several ion channel drugs were approved by the FDA. For example, esketamine, an NMDA receptor antagonist, used as an antidepressant, or brexanolone, a GABA receptor agonist, used to treat postpartum depression in women. These drugs will definitely bring money to the field.

On the other hand, there is a lot of disappointment in the drug development on Nav1.7. Many companies had invested in Nav1.7 as a target for the treatment of pain. And it would have been a game-changer but until today it didn’t realize its potential. There could be different reasons for this. One is that Nav1.8 is upregulated in patients with pain so if you specifically inhibit Nav1.7 it will not be as effective. Another reason is that in order to be effective, a drug should apparently inhibit a 100% of Nav1.7, which is difficult to achieve. Maybe it’s a bit of both, I don’t know, but here we can clearly see the drawbacks of a “gene to target” approach, which was the primary drug discovery approach for decades.

But if you now look at esketamine and brexanolone, these drugs were already on the market before and they got repurposed. I would call it a “drug to target” approach instead of “gene to target” – we have a molecule which leads us to the target. We’ve seen that those molecules can be effective and now companies are optimizing the drugs to be more subtype specific to have less side effects. And I think that this can help to build new projects and to bring new money into the ion channel field.

The development of personalized medicine for patients with channelopathies is another great application of ion channel research. I would like to give you one example from the University of Copenhagen. Kirstine Calloe, was closely working together with clinicians on an interesting case of a Danish family where members died early because of heart failure. Sequence analysis in these patients revealed a sodium channel gain-of-function mutation. Therefore the idea was to try treating the patients with sodium channel inhibitors, like flecainide. The treatment of many of these patients has been changed ever since and they are now in much better condition (see here). This suggests that by looking at the mutations causing the disease, this can result in a better choice of medications for patients. I think that ion channels are particularly suitable for this, because you can easily see gain-of-function or loss-of-function mutations by measuring the ion channel function directly.

OK. I see that you are rather positive about the state of ion channel industry and are optimistic about its future.

Yes. I would say I’m positive, yes. And actually, there are also other things which are very motivating. For example, we had a poster at the Biophysical Society meeting and were presenting pharmacological results on CTFR measured with the SyncroPatch. We used the available drugs from Vertex in that study. A woman who came to the poster said: “Oh this is very interesting, you’ve measured the action of this drug on CFTR. You know, I have cystic fibrosis and I’m taking this drug, and it’s fantastic. My life is so much better now.” I can tell you, that when you’re talking to a patient at your poster – this is just pure energy. You really see that it’s useful what you’re doing, and you feel a lot of satisfaction that your research could really change something for the better.

Well, as you are so positive about the ion channel industry, imagine that you are starting a new company in the ion channel field now. Could you tell me about this company?

Hmm, that’s a good question. If we would talk about technology, I think I would concentrate on things that are important but not so easy to do. One thing would be combining fluorescence with patch clamp measurements. There is also a lot of interest now in intracellular membranes such as lysosomes or mitochondria – I mean to find an easy way to patch them. So, I would look at these niches where you don’t have any or almost no competition, because when you’re small and you’re just starting something it’s hard to compete with bigger players, so you need to work on something difficult.

But if I would have to deal with drug development, I would go for the NMDA receptors in the field of depression.

Your answer is so specific. Thank you for sharing these ideas. I think many people will find them interesting. And now, let’s talk about the automated patch clamp (APC), and more specifically about APC in academic institutions. You know, many scientists are still rather skeptical about the use of APC in academia. Could you comment on this?

Yes, I know, and we are trying to change this situation. I visit conferences, institutes, labs and illustrate the possibilities of APC, and also the limitations. We do a lot of live demonstrations to show our instruments in action, and I’m happy to come to any interested group to give a presentation on how you can use APC in your research. We at Nanion produce great APC instruments that can really make many academic projects much more productive. And any electrophysiologist who had ever seen our instruments in action just “fall in love” with them. Me personally, I love them. Because they make you so much more effective. I understand that some people are still frustrated with their negative experience of using some old APC systems from manufacturers that do not exist anymore. But these times are long gone and we need just to leave it behind and move forward. Technology is rapidly developing and modern APC robots are doing their job just fine.

“Automated patch clamp makes your experiments faster and easier, and you can really concentrate on your genius brain and great ideas about ion channels.”

ANDREA BRÜGGEMANN

Let me give you some examples of how people in academia use our highest throughput APC machine, the SyncroPatch 384. And I think that the lab which has used it the most is Al George and Carlos Vanoye from Northwestern University Feinberg School of Medicine, Chicago, USA. Recently, he published a study of pharmacology on iPSC cells using the SyncroPatch 768PE (see here). Al’s group also uses the SyncroPatch to look at patient mutations to understand whether these mutations are disease-causing or are silent (see here).

Another example is at Vanderbilt University, where they also look at mutations, but also perform drug screening with the SyncroPatch 384 (see here). Then, in Nantes, France, Michel de Waard studies the effects of toxins on ion channels using our SyncroPatch (see here). In Wollongong, Australia, David Adams uses the SyncroPatch for toxins and ion channel mutation studies, but he also offers any university groups or also companies to use his SyncroPatch 384 (see here). Rocio Finol-Urdaneta, the lead scientist in Adams’ group, runs the APCs for her own projects but also as a service for a bit more than the consumable price. At the University of Copenhagen, Nina Braun characterized (during her Ph.D. with Stephan Pless) 128 mutations of the ASIC1 channel incorporating 3 different noncanonical amino acids at every position (see here). These are just a few of the many examples of how our high throughput instruments are used in academia.

OK, but all these projects you were talking about are focused on mutations and/or drug testing. And they really resemble some industrial projects. You know that very few labs have such large-scale projects. So, if we talk about pure academic fundamental research, can automated patch clamp be useful here?

Yes and no. It depends on a project. What I’m trying to say is that automated or planar patch clamp cannot be used for everything. In the case of automated patch clamp you cannot optically choose the cell you want to patch. If you want to patch a certain cell in your dish then planar patch clamp is probably not a perfect setting for your application. It is possible to use cell sorting (FACS) prior to your measurement, but it adds an additional step. On the other hand, it might also be a benefit to select a cell for your measurement by a totally unbiased manner.

By using a planar patch-clamp system you will need very little of the compound and also you’ll have a very easy access to shine light on your cell.

ANDREA BRÜGGEMANN

But there are also examples where the SyncroPatch allows you to do measurements that cannot be performed with a conventional rig. One example is the intracellular solution exchange (see here). If you want to apply some drugs from the intracellular side it’s not so straightforward to do on a conventional rig. Another example is patching red blood cells. It’s very tedious using a pipette, but it’s relatively easy on a planar surface. It has been done with the SyncroPatch, Patchliner and also the Port-a-Patch. Even comparing red blood cells from a patient with a Piezo mutation to red blood cell from a healthy control (see here). One more advantage of a planar patch clamp over the conventional rig is the small volume you can work in. So, the working volumes for our planar patch clamp systems range from 5 µL for Port-a-Patch to 20 µL for Patchliner. But when we think of conventional rig, we are usually talking about mL not µL, roughly a factor of 1000. For the work with toxins, antibodies or photo-switchable compounds for example, that makes a big difference. By using a planar patch-clamp system you will need very little of the compound and also you’ll have a very easy access to shine light on your cell.

Another situation when the higher throughput can be very helpful in academic research is when you work with patient cells and iPSC-derived cardiomyocytes. These cells are rare and quite expensive. Usually, those cells are only good for 4-8 hours; therefore time can be a very important factor. The higher throughput allows you to perform more measurements in this given time frame.

And there is one more thing. Let’s say you have 10 ion channel mutations you want to look at. For example, you want to study their kinetic behavior. So, when using your conventional rig, if you do one mutation per day – you are good. So if you would do 10 mutations with all the controls in two weeks you would be extremely good. That means that the room temperature within these two weeks wouldn’t always be the same, the solutions would not be identical, the culture conditions in your incubator would not be identical either. But if you do it with the SyncroPatch 384, you have identical room temperature, identical solutions, and identical culture conditions, because you can measure all 10 mutations including the control in one run. By removing this background variability you can see more subtle changes in your mutations. And also you can easily do a higher number of n.

Well, I see there are some clear advantages here.

There are also limitations. Brain slices or adult neurons for example. To measure cells on a planar surface, it is necessary to harvest the cells to a single cell suspension. In the case of neurons, there is a big risk in losing the dendrites, which might make it difficult to study dendritic channels.

“Automated electrophysiology has great capabilities, but also its limitations. It is important to see for your own project how you can make use of the benefits and avoid the limitations.”

ANDREA BRÜGGEMANN

Great. So, when we are talking about automated patch clamp, we are talking about rather expensive things. In what price range are we?

Our cheapest and smallest patch clamp instrument is “Port-a-Patch mini” that is in the range of 20,000 Euros. The Patchliner ranges between 100,000 and 300,000 Euros depending on configuration and add-ons, and finally the SyncroPatch starts at around 600,000 Euros and you can have it with two modules/768 amplifiers and it can go up to a million depending on what automation you want to have.

100,000-600,000 euros – that’s a lot of money. So, how can academic scientists afford such an expensive APC system? Where do they find money for this?

In Germany, for example, DFG has an instrumentation grant. The NIH also has something like that. A SyncroPatch is often financed by the application of several groups to run it in a core facility. Similar to a cryo-EM. And if it’s possible to finance a cryo-EM through grants, it’s for sure possible to finance a SyncroPatch 🙂

We see more and more SyncroPatches in core facilities around the globe. As for the Patchliner, most of the time people have it in their own labs. The very first two Patchliners did go to David Beech’s Lab and they’ve used it a lot for different projects (see here). Also, Steve Petrou in Melbourne, Australia, uses Patchliners heavily on ligand- and voltage-gated channels for all kinds of characterizations (see here). So, this is often financed by one lab through the instrumentation grant.

OK. Let’s imagine that we’ve got money for an APC machine. What are the main players on the APC instrumentation market? What can we choose from?

Well, I’m biased – that’s very clear. But as you ask, the number one for me is, try to guess it, Nanion Technologies. And number two is Sophion. There is no doubt Sophion’s QPatch is a great success worldwide. The QPatch can be in 16 and 48 channels so that’s also something that lies in between the Patchliner and SyncroPatch. In the high throughput field, I mean recordings from 384 wells and more, I think the Nanion’s SyncroPatch 384i outruns the Sophion’s Qube 384, and leads the field in industry, safety and also academia.

And actually, there is one more player – Fluxion. They mainly concentrate on ligand-gated channels because of their intelligent fluidics. I would say they have their niche where they are successful but their market share is rather small compared to Nanion’s and Sophion’s. All the other players are gone. Molecular Devices used to be the biggest player in this field I would say ten years ago but they decided to step out of this market. Flyion, Cytocentrics and Cytion – all three do not exist anymore.

Both Nanion and Sophion develop rather similar planar patch clamp technologies. So, how can one discriminate between these two companies?

The obvious difference is the substrate. We went with borosilicate glass, the QPatch works with silicon, and the Qube 384 works with the plastic surface. Another thing is the software approach. At Nanion we’ve chosen a more academic and flexible approach. You can change any parameter at any time, so it’s a very open system. You can stop the robot at any moment and play with the electrophysiological software. The robot is sort of independent from the recording software giving you a total control over the experiment. Planning the measurement and setting it up is usually done by an electrophysiologist, but for running the machine you don’t have to be specially trained. Sophion did go the way that it’s more one piece, so everything is programmed as one concept. And there is a benefit to it – it makes it probably less complicated for the user, but it also limits your possibilities in which experiments can be performed.

OK. And what options exist for people who don’t possess the whole amount of money needed to buy the APC system? Is it possible to rent of lease APC systems or is there a market for used APC machines?

Nanion is very flexible, when it comes to this question. We’ll do as much as we can to make sure the customer gets the instrument they need. If that means renting it for 6 months whilst they get data to put into a grant application – we’re open to those ideas. We also help our customers to get preliminary data for their grant applications and provide flexible leasing options. We have a lot of leasing projects, so that you can lease an instrument with a monthly rate and after two-three years you own the instrument. Most of CROs do it this way because they often have difficulties to finance it from the beginning and so they finance it with the money that comes in. But also we see this in academia depending on what projects they have. And even pharma companies do it depending on their budgeting.

As for used instruments, you can find some used PatchXpress or Ionworks instruments from Molecular Devices on the market, but it’s very rare that you can find some used machines from Nanion or Sophion. People keep it, people use it.

And how about giving your SyncroPatch 384 for free? I’m talking about Nanion’s SyncroPatch Research Grant that you proposed this year. How can you just give away the SyncroPatch (which starts at around 600,000 Euros) for free? What’s the idea?

This idea started actually with a SURFE²R. The SURFE²R is an instrument measuring activity of membrane transporters. The technology is great, but people in this field are used to use the established methods they have in their labs and they don’t even think of measuring the current directly. And so, we decided to make an offer, so that people could apply for an award and get the SURFE²R into their lab for 6 months.

People wrote fantastic proposals to us so in the end we actually gave three machines. And researchers realized how useful the SURFE²R is and now they are giving presentations and did great publications showing the data obtained with the SURFE²R. So, after the success of the SURFE²R we decided to do it with the SyncroPatch 384i as well. As we were discussing, many groups are still skeptical about how automated patch clamp can be useful for their academic research. And some of them still remember their previous negative experience with old APC systems. We want to change this situation.

We already partner with more than 200 academic institutions and we want to show that modern automated patch clamp systems are reliable and effective machines you can count on.

ANDREA BRÜGGEMANN

We already partner with more than 200 academic institutions and we want to show that modern automated patch clamp systems are reliable and effective machines you can count on. That’s why we are giving people the chance to get our SyncroPatch 384i, for 9 months in their lab, completely free of charge, including 125 chips. And I can tell you that people applied with fantastic projects. They share their ideas on what they want to do with the machine so we now can take this information to optimize the machine for these kinds of measurements and make it more suitable for their experiments. From our side, we see this as an investment in the future.

So, we now see an increasing interest in APC from both industry and academia. And I cannot help but ask you: Should electrophysiologists start worrying about their jobs because of development of APC technology?

No, and I think it is the opposite. When in 1992 I learned to do molecular biology people were using the phenol-chloroform method for DNA preparation. And then QIAGEN came with the columns. Did these columns destroy the job of molecular biologists? No, it was the opposite, it actually made it easier and made it applicable for more people and made it even a bigger success. So, your success as a molecular biologist is not about the preparation of the DNA, it’s about your smart experiment. It’s your project that makes it a success, not the technique. And I think the same is true for the electrophysiology. My success is not that I can patch clamp. My success is that I can make the connection between sodium channels and pain or NMDA receptors and depression, for example. It’s not at all that I can patch a cell.

I think that the automated patch clamp does the same thing for the ion channel field as QIAGEN’s columns did for the molecular biology field.

ANDREA BRÜGGEMANN

So, actually I think that the planar/automated patch clamp does the same thing for the ion channel field as QIAGEN’s columns did for the molecular biology field. This technology makes your experiments faster and easier and you can really concentrate on your genius brain and great ideas about ion channels. For example, when the HCN channel was cloned, the person who was smart enough to do a negative voltage pulse (instead of positive) was then the person who was able to measure HCN current. It’s not about the technique, it’s about your brain.

I see that you’re very optimistic about it. But you wouldn’t deny that with all these automation and robotization trends many jobs are at risk of being replaced by robots.

Well, I’m a person who likes technology, so I have a very positive idea about robotization. Have you ever been in a car manufacturing environment? There is a lot of robotization in this field. And if you look at jobs that robots are doing, these are not the jobs you want to do. So, actually I think robots are doing exactly that part of the jobs. Personally for me, I don’t want to do any of the jobs that robots do. In my house I have a vacuum cleaner robot and I have it because I don’t like to vacuum clean. And so I’m using robots in the case when I think I can spend my day better than that. Other examples are my washing machine or my dishwasher. I’m thinking about my grandmother – when the washing machine was invented, was she scared over washing machines taking away her daily work? No. It’s just a great relief. So, the things that robots can do – they don’t scare me. By assigning a part of my work to robots I have more time to concentrate on things that I can do with my brain or I can go hiking, skiing, biking, whatever. So, I advocate for the development of automated technologies. By saying all this, I do not deny that many workers with lower secondary degree education will be affected by these robotization trends. And I think that it’s very important to empower those individuals through reskilling or upskilling to meet the needs of labor market.

That’s a good point. So, where are we going in terms of APC technologies? What’s the industry trend?

In my opinion, it’s not going to go even higher throughput. I think with 768 wells we are at the limit. I don’t think anybody is going into 1536 wells. We are going to learn more and more about different ion channels so that we are going to be able to measure all of them. Some of them are trickier than the others and so we need to make screening technologies applicable to as many ion channels a possible, including intracellular ones and highly regulated ones. The trend is also to combine different capabilities into one instrument to make it broader applicable. This includes temperature control, intracellular solution exchange, light control for optogenetics and also fluorescence measurements.

And then, the field of ion channel reconstitution is also increasing with all the cryo-EMs and this will have a direct impact on our ability to reconstitute functional ion channels in artificial membrane systems for subsequent electrophysiological analysis. Another big topic under development is interaction of ion channels with lipids focusing on how the lipid composition is influencing ion channel function. Then, the interactions between transporters and ion channels are gaining more attention nowadays, and this requires the development of new approaches.

I also think that we are moving towards using more patient material instead of overexpression systems. And this is very important for the development of personalized medicine where you really deal with patient mutations and look at how pharmacology can be repurposed to help that particular patient.

That’s very interesting. Is this something Nanion is working on now? Could you share some “secrets”?

Well, one project we are looking into, is the combination of fluorescence and electrophysiological measurements with a planar patch clamp. In January 2020, I visited Pancho Bezanilla in Chicago for proof–of–concept study. Based on the Port-a-Patch we assembled a prototype that was capable of the simultaneous recording of the electrical and optical signal. Our plan was to present these results at the Ion Channel Gordon Conference to see what people think about this, and if they would consider it useful. Maybe next time 😉

Another project that we are interested in is improving our abilities to measure intracellular membranes, e.g. lysosomal ion channels. Although it’s possible to patch lysosomes on the Port-a-Patch, it’s not easy and there is room for improvement (see here).

So, you see, we are mostly working on making our instruments applicable to more projects. We also collaborate with people having an idea on how we can use the CardioExcyte 96 system (primarily designed to record extracellular signals from cardiomyocytes) in a different way. We have several ideas around this, but I cannot share them at this point. Stay tuned, and you’ll know about them soon.

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I’m thankful to Andrea Brüggemann for taking the time to talk with me and sharing her interesting thoughts.

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Pictures by Andrea Brüggemann.