Hugues Abriel is a professor of Molecular Medicine and Co-Director at the Institute of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Bern, Switzerland. Prof. Abriel is also the head of a research group investigating human diseases caused by malfunction of ion channels (channelopathies). He is also the coordinator of the NCCR TransCure – an interdisciplinary Swiss research network focused on membrane transporters and ion channels.
Other than that, Hugues speaks fluently five languages, leads crowdfunding campaigns to support African scientists, organizes every second year an international Channelopathy conference, provides voluntary medical assistance to patients at risk confined because of the COVID-19 crisis, and feels truly privileged to live and work in Switzerland.
I spoke with Prof. Hugues Abriel about his career, ion channel research in Switzerland, industrial collaborations, consulting, crowdfunding in science, and more. The conversation with him was very enriching for me and I hope many scientists (in particular, young scientists) will find something useful in this interview.
Have a good read.
So, Hugues, let me start by asking you about your past, about the trajectory which brought you to the place you are at now. How did you become interested in ion channels? Was it during your Ph.D. or University studies?
Well, actually, I remember very well that day when ion channels attracted my attention for the first time. I was a biology student at the ETH Zurich and I think I was in the second year. It was a biochemistry class and our Professor Ernesto Carafoli – I remember this very well – was extremely excited when he mentioned the fact that there has been a discovery that one can record the activity of only one single channel with a glass micropipette. Obviously, he was talking about the work of Neher and Sakmann. He was thrilled about the fact that there is a technology that makes you be able to record the activity of just one protein, one molecule, and to get a few picoAmps out of this one molecule. And somehow, you know, it stayed in my head, resonated with me. Later on, there have been many other anecdotes in my scientific life that brought me to ion channels. One of these is when as a medical student, in order to earn a little bit of money, I had been participating in Phase 1 clinical trials as a healthy volunteer. You know, these Phase 1 “first-in-human” studies are designed to test the safety and side-effects of drugs. So, one of the drugs that I had to test was a psychotropic drug, and at that time pharmacologists already knew that psychotropic drugs might lead to heart arrhythmias and QT interval prolongation on the ECG. Therefore, during the time I was receiving these drugs, I had to have many electrocardiograms to be sure that I would not go into troubles with my heart. And I remember, when I was discussing about this drug with Prof. Thierry Buclin, he told me: “Oh, you don’t know about drug-induced long QT syndrome? You have to know it because this is a drug that blocks potassium channels in the heart.”
Wow, it looks like destiny brought you to ion channels.
Yes, somehow. But, you know, I looked for it somehow. My brain has always been trying to make connections and to put things together, and therefore these “ion-channel-moments” in my life did not go unnoticed but provoked thinking and expanded my scientific interests.
So, after getting your master’s degree in pharmacology, you then obtained an MD degree and a Ph.D. degree in physiology. What motivated you to get this dual degree training? What was your plan at that moment: to become a doctor with a strong scientific background or a research scientist with a strong medical background?
That’s the second. Actually, I’m a scientist and I am attracted by all aspects of biomedicine. I was interested in ion channels, but in order to be able to do really what I wanted to do, I had to have also a medical background. In addition, medical education allows for a better understanding of the clinical needs and challenges, which is important if you really want to understand your value as a scientist in medicine. But I have to say that, whereas my main motivation and drive is science, I’m also extremely interested in clinical medicine and I’ve worked as a doctor for two years after my medical studies at the University of Lausanne. And I’m still trying to keep something related to clinical medicine. Any clinical case, where I can directly or indirectly contribute to, is a strong motivation. When I was closer to my colleagues in cardiology, I interacted with patients having cardiac disorders related to ion channel mutations. I tried to do my best and to explain to them what ion channels are and why, because of these mutations, they may have cardiac disorders. But ethically, you know, you have to be quite careful with what you say to patients and consider the level of confidence of what you know and don’t know. Because most of the time in clinical work it’s more about not knowing things than knowing them. Currently, I’m helping old friends, with whom I’ve been studying medicine, to take care of patients that are confined because of the COVID-19 crisis. I call them, talk to them and do a bit of telemedicine with these patients. That’s a very nice feeling when you have a patient telling you: “Oh, thank you for your call. It’s nice to feel that someone is taking care of me.” It’s very fulfilling.
That’s great that you can leverage your medical and scientific expertise to help people in need, especially now, when so many people are confined in their homes. So, it seems that despite being a scientist, you still keep strong connections with medicine. This is even reflected in your current title – Professor of Molecular Medicine. I’m curious, what’s it like to be a professor of molecular medicine? What’s your typical day?
I’m multitasking. As a University professor, I have three types of tasks or duties. The first one is teaching. You can teach University students and provide mentorship to young scientists in the lab, including Ph.D. students and postdocs. I don’t teach much. Actually, I teach very little for a professor because I’ve too many managing duties. I give a few classes: “Biochemistry of the Nervous System” and “General Biochemistry” for medical and pharmacy students. If you ask me whether I like it – yes, I do like it. But, you know, you shouldn’t underestimate the work it implies, if you really want to be a good teacher. And it’s a bit frustrating not to have enough time to spend on preparing excellent lectures. So, that’s the teaching. The second duty is doing research. In my case, doing research doesn’t mean physically doing experiments. I’m not currently pipetting anything or doing patch-clamp experiments. The last time I did a patch-clamp experiment was some 15 years ago. So, for me, doing research is mainly supervising students, reading/writing/reviewing papers and writing/reviewing grants. That’s the second aspect. And the third one is the so-called “service”. You have the service task as a professor in academia. This is very broad. If you are a doctor, your service is to treat patients. If you are not a clinical person, you are involved in a lot of management tasks and, in fact, for about ten years I’ve been spending much time doing this. I’m coordinating, directing, and managing research institutions. I’ve been the director of a large clinical research department, as well as the President of the Division for Biology and Medicine of the Swiss National Science Foundation (SNSF). For the last eight years, I’ve also been a member of the SNSF research council. And it means that we review hundreds and hundreds of grants per semester from scientists mainly working at Swiss institutions. This involves a lot of strategical thinking and coordination, quite a bit of politics, and… it takes almost all my time. It’s hard to talk about a typical day, but it’s quite possible that I would have all three aspects of this academic work in one day.
So, you are not doing experiments by yourself anymore. Do you miss it a little bit?
Actually, I cannot really say that I miss a bench or a setup. I’m not a bench person. I’ve been doing benchwork for enough to understand it very well, but I was always more interested in thinking about the concepts and reading/writing papers or projects, rather than doing western blot, for example. Nevertheless, I like to join students or colleagues while they are patching and discuss the results in real-time. I try to understand the details of every process I’m dealing with, and that’s what I teach to my students.
What’s the main focus of your lab just now? What problems are you trying to solve?
In general terms, we try to address questions about how ion channels are related to diseases. And over the years, we have been interested in genetic channelopathies of excitable cells, mainly cardiac cells. But we also had projects on ion channels expressed in other tissues, for instance, in the peripheral nervous system or in skeletal muscles. We have been working mainly on the family of the voltage-gated sodium channels with a main focus on the cardiac isoform of Nav1.5 channels. Many mutations in these channels have been described, and we try to contribute to the characterization of these mutations in the context of the congenital long-QT syndrome, Brugada syndrome and other types of syndromes.
One aspect that I like very much in the lab is that we get requests from clinical scientists (geneticists, cardiologists or neurologists), when they discover new variants in ion channel genes and they want to understand whether these variants are causing the disease that they’re observing in their patients. I’ll give you an example. This is an example that linked me to a very good friend of mine, Prof. Elena Zaklyazminskaya, a geneticist from Moscow, Russia. She recently mentioned to me that there was a family in Poland with both father and son having cardiac conduction disorder and carrying a mutation in a gene called TRPM4, which is also a cardiac sodium channel. She also told me that they don’t know whether this mutation causes the disease in these patients. Then, a Ph.D. student in the lab generated this mutant TRPM4 channel and expressed it in cells. He observed that this mutant channel was not expressed on the cell membrane. We propose that this could be the reason why these patients that are heterozygous for this ion channel gene variants have cardiac conduction slowing.
So, somehow it is part of a clinical diagnostic process. We help our clinical colleagues to increase their confidence that these genetic variants cause the disease. This is important in terms of genetic counseling. It means, for example, that if a person is planning for a baby, he or she has to know that he/she is a carrier of a variant that may be leading to a hereditary disease.
So, there are two main ion channel topics in your lab: Nav1.5 and TRPM4. How come that you selected these two channels for your research? My question is about your strategy. How do you determine your research direction? Does it come from industry, hot scientific topics or maybe it’s based on the scientific interests that you brought from your postdoc?
It comes from years of experience and a bit of, let’s say, trial and error. First, you need to start somewhere and see if you like it or not. I applied to a postdoc to the lab of Prof. R. Kass (at Columbia in New York) working on sodium channel mutations and then I started to develop my own network of scientists who could provide me with mutations or are interested in collaboration. You start to see opportunities in your field and therefore continue advancing in that direction. You know, you don’t have to take it negatively, but this is a bit of an opportunistic approach. On the way, you test some other directions. For example, we’ve also characterized mutants in KCNQ1, HERG, and calcium channel genes. But finally, you need to focus somewhere, where you are most productive and efficient, where you see opportunities, where you are most excited about the work you do. For me, these are the Nav1.5 and TRPM4 channels.
What is the most satisfying discovery you’ve made since you started working as a scientist?
I think it goes back to the first high-impact paper, and this was the first channelopathy I was working on, which was due to the mutation in the non-voltage-gated sodium channel, the ENaC channel. With my friend Prof. Olivier Staub we discovered that ENaC mutations, found in patients with Liddle’s syndrome, were actually disrupting the interaction with the ubiquitin ligase Nedd4, leading to increase in channel numbers at the cell surface, increased Na+ reabsorption by the distal nephron, and hence hypertension. That’s a Journal of Clinical Investigation paper published in 1999 – 21 years ago. You know this is like a “first time”, somehow.
Yes, that’s a nice paper. And what about the “multiple pool model” that you described in one of your reviews. Your latest articles about distinct pools of sodium channels, I think, go in line with this model. Could you tell me a little bit about this?
Of course! Early on, about 20 years ago, we started to be interested in proteins interacting with ion channels. We were focusing on Nav1.5 and many of its interacting proteins were identified to be either enzymes (so it means that they modify ion channels), or proteins that are important for targeting ion channels to specific membrane compartments. So, it was more and more clear that alpha subunits of ion channels were not isolated, and they need to interact with other proteins in order to have the channel functioning properly, as well as to be targeted properly in specific membrane compartments. And then, we discovered that the proteins that are important for lateral targeting of sodium channels in cardiac cells were proteins that we would not find at the intercalated discs. So, the lateral pool is associated with the syntrophin/dystrophin complex, while at the intercalated discs it is SAP97 or MAGUK proteins that complexed with sodium channels. But in fact, this is still a very naïve model and we now come up with more distinct types of pools with even more interesting partners. Recently, we have also been interested in another cardiac cell compartment – the T-tubules, which are invaginations of the membrane into the cardiac cells. The latest evidence shows that there is also one sodium channel pool there and we don’t know yet exactly which are the interacting partners. This is still an open question. So, in summary, there are populations of Nav1.5 channels that are complexed with specific channelosomes or macromolecular complexes. It means that different pools of Nav1.5 channels could have different functions in the cell and could be regulated differently depending on intracellular localization. Now, we are trying to understand what the physiological and pathophysiological roles of these different complexes are.
Tell me about your team. Who do you work with? Who’s helping you in the realization of your scientific projects?
My team evolves over the years. We are a small-sized group. We are no more than 10, including 2-3 lab technicians, 2-3 Ph.D. students and 1-2 postdocs (see the website of the Hugues Abriel Lab here). When I started my lab in 2002, 18 years ago, I was very close to my students, so I would be discussing projects every day with them. Now, if I can do it every week, it’s already good. But I’m extremely privileged to continue working with my first Ph.D. student from France, Dr. Jean-Sébastien Rougier, who’s now doing almost all supervision in the lab. He was extremely good at performing his Ph.D. thesis and, fortunately, after his postdoc in London, he returned to the lab, and now he is my “bras droit” (right-hand man) – as we say in French. He is really the person who makes us successful and he is present in the lab every day, every hour, every minute to answer questions and help younger students to work on their projects.
You mentioned some collaborations. Who do you collaborate with?
The scientists that I like to work with the most are those that are not doing exactly the same thing as me. They could be clinical scientists, as I mentioned before, cardiologists, neurologists or geneticists. Further, I collaborate with scientists from different countries, including Europe, Russia and the USA, and then for about 6-8 years, I’ve also been working with medicinal chemists and structural biologists in the framework of the Swiss NCCR TransCure network. Chemists help us to find compounds that may be used as tool compounds to block/activate TRPM4 channel and recently, we also started to work on structural aspects of TRPM4 using cryo-EM technology. Broadly speaking, this is the interdisciplinarity that I’ve been able to benefit from in recent years.
Any industrial collaborations?
Yes, there have been some industrial collaborations, mainly with Novartis, in the frame of the TransCure consortium. But I have to say that I’m a strong supporter of academic free and open science. I have a hard time with patents that you get using the money from the public. I sometimes have “fights” with my colleagues at the university who say: “Oh, we will not publish it because we first have to patent it.” I think it’s not very ethical. You got the money from the taxpayers, so your discovery has to stay public. Therefore, collaboration with industry is interesting for me if the industry understands this way of thinking. And I very much welcome the open innovation trend in the industry. It means that you collaborate with industry as if this would be an academic lab. It’s open, you sign nothing, no disclosure, no confidentiality. You just work as if this would be your academic neighbor. You learn something, they learn something, they do whatever they want to do with it and you have your own papers. I like this kind of collaboration.
Could you tell me more about the technologies you use in your lab. Are there any novel technologies that you’re introducing in your research?
Well, I’m balancing between interest in new technologies and being a bit conservative about technologies. I’m not too much into technological development – for me, the focus is on obtaining meaningful results. I want to learn something about biology or diseases. Among the novel techniques that we are using more and more is single-molecule high-resolution microscopy. We’ll soon have a paper on clusters of sodium channels where we used this technology. This is the result from a collaboration with Prof. Mario Delmar and Prof. Eli Rothenberg (New York University). We also study various genetically-modified mouse models. For instance, we have several knock-in mice that are mimicking human diseases, because the genes that are mutated are the same as the ones mutated in humans. But I have to say that working with such animal models takes a lot of work and resources. It’s very expensive. So, I would like to change a little the way of doing these experiments in the future. I would rather go to what’s more biophysical, more molecular, and I really would like to develop single-channel and lipid bilayer technologies in the lab.
What about your plans and goals for the next few years? You said that you would like to develop some biophysical techniques in your lab. Anything else?
Well, the main goal is to take a sabbatical leave and to spend almost one year in three French-speaking African countries: Congo, Comoro Islands and Morocco. My goal is to test a new portable nanopore-based DNA sequencing technology developed by Oxford Nanopore Technologies, Oxford, UK. In fact, this technology is related to ion channels. It uses protein nanopores incorporated in polymer membranes and measures the changes in ionic current through these nanopores, as DNA goes through them. This information about the changes in ionic currents allows you to sequence the DNA molecules. I want to use this technology to sequence candidate genes in African countries. And one of the genes I want to sequence in Africa is CFTR, because at present, very little is known about the variants of CFTR in African countries.
Since 2014 you’ve been involved in collaboration with Congolese scientists from Kinshasa. I would even say that you played the role of a big brother for these scientists, helping in obtaining funding via the crowdfunding platform as well as organizing their short-term visits to Switzerland. Could you tell me more about your experience with the crowdfunding of scientific projects? Is this a viable alternative for scientists from developing countries to obtain some funding for their scientific projects?
I have been able to help at least two colleagues from Kinshasa, Congo, to advance their projects through crowdfunding. We had three campaigns on the Swiss crowdfunding platform wemakeit, giving them the opportunity to get about 10.000-15.000 Euros. This allowed them, for instance, to be able to go to a workshop in the USA or visit the lab at the University of Bern, which was the case in 2015. I think that crowdfunding works well for that type of projects. It’s quite a lot of work, but it’s very rewarding to do it. Also, there is a science communication aspect into it. For example, you have to make a video explaining why you want to do this, why this is important. So, it could be very beneficial if you have people passionate about science communication in your team. Fortunately, our scientific officer, Dr. Patricia Teixidor Monsell, is an experienced editor helping scientists to communicate their discoveries to the general public. Patricia helped a lot in organizing these campaigns.
However, if you want to get a large scientific project being funded, it will be much more difficult to get funding via crowdfunding platforms, unless your project is something that attracts, that is extremely relevant to the general population. In the case of basic research, I’m quite convinced, it will most probably not work. So, we still need big philanthropic or national funding agencies to help our research.
You’ve mentioned science communication. In my opinion, many scientists still prefer to stay in their small world and underestimate the importance of science communication to the general public. What are your thoughts on that?
You know, this has been a process for me. At the beginning of my career as an independent scientist, I was very much focused on, let’s call it “success”. Then, I realized that there is a broader aspect to science. There is an ethical aspect of science. Following multiple visits in developing countries, I realized how privileged we are here in Western countries and in Switzerland, in particular, to get a large amount of funding. Really, we have a huge privilege, and we could get even more funding from our fellow citizens, taxpayers. And it means that you have a responsibility linked to that. I was thinking about this and it brought me to understanding that one has to communicate science in a way that is useful. I’m not doing too much of large public outreach and I’m mostly focused on the outreach within the ion channel community. You know I’ve been organizing the international Channelopathy conference every second year – that’s my baby for almost 10 years now, and for me to get something done in that sense of outreach is even more rewarding than to have good papers being accepted.
From your LinkedIn profile, I’ve learned that right after your postdoc in the USA you worked as a Director of Cell Biology Department at Cytion. This information has answered my question if you ever considered industry for your career path? Apparently, you did. Could you tell me more about this experience?
Yes, you’re right – I wanted to try myself in industry. So, in February 2001 I joined Cytion – a startup that developed automated patch clamp solutions for ion channel drug discovery. In summer 2001 it was acquired by Molecular Devices. Cytion had an interesting development project. It was not research. And what I realized, while working at Cytion, is that I’m “a research person”. I like concepts, I like to learn something new. I’m not a person who could spend years to adapt new technology. I have a lot of respect for industrial scientists. It’s important what they do. I’m just not that kind of person. But overall, that was a very valuable experience that helped me to understand that a researcher lives inside of me, and so I need to pursue an academic career. And after that, when I found my path in academia, I did not regret a single day that choice.
That’s interesting. And what about consulting? Do you provide consulting services to companies? If yes, how does it happen?
I’ve done that a few times for companies in France, Switzerland and the UK. It is rewarding because you understand that you have a unique expertise that can be useful for companies to assess and develop projects. This is quite academic in a sense. You can be asked to review a project that has been submitted to a company, or to give your opinion on the company’s internal project. On one occasion I’ve been invited to the meeting in a company in Switzerland where I was not the only expert and there were other consultants as well. We had to give our opinions and to challenge the US scientist who was proposing his project to the company. Another example – I was invited to a company in the UK where I spent two days doing a kind of due diligence: we were interviewing the employees, analyzed presentations from different projects in the company’s portfolio and so on. Here again, it was very similar to what I do in my academic environment.
You live and work in Switzerland. A beautiful country, famous for its watches, banks, chocolate, lakes, mountains. But, how are things going with ion channel research in Switzerland? Any ion channel networks, associations, local meetings, etc.?
I’ll start with what I like to say about ion channels in Switzerland. We have a few pioneers of electrophysiology in Switzerland. One is Prof. Silvio Weidmann (1921-2005), who was a director of the Institute of Physiology at the University of Bern. He was the first to record the action potential of a cardiac cell (J Physiol., 1951). Another pioneer, who is still living, is Prof. Harald Reuter, who was a director of the Institute of Pharmacology at the University of Bern, and he was the first to record calcium currents under voltage clamp (J Physiol., 1967). He also was the first to show the importance of a slow calcium current for the plateau of the cardiac action potential (J Physiol. 1970). So, those are our fathers of electrophysiology in Switzerland.
And then, we have quite many groups working on ion channels. There is a community. I don’t know about the density of ion channel scientists, but I think we are doing pretty OK. There is no ion channel society and we don’t have associations, but recently we were thinking about the creation of a section of Membrane Transporters and Ion Channels within the Life Sciences Society of Switzerland. This is one of the projects we have in mind. We’ve already started to collect the number of possible members and we came to about 300 possible members.
Also, as I said before, we have an interdisciplinary research network focused on membrane transporters and ion channel research – The National Centre of Competence in Research (NCCR) TransCure. TransCure network unites 15 research groups from four Swiss universities and brings together structural biologists, physiologists and chemists. It was established in 2010 and is funded by the Swiss National Science Foundation until 2022. So, now we’re thinking about the continuation of this TransCure Project after 2022.
We can say that currently, you are on top of the science career ladder. And, what’s more important, you love your profession. Have you managed to convince your children to become scientists?
Actually, it wasn’t my goal to convince my kids to become scientists. My kids are 25 and 23. My son, Samuel, will most likely not be a scientist. He’s more interested in writing, history and photography. And my daughter, Mara, surprised me two years ago because she was more into arts, dance and then when she turned 19, she told me she wanted to study medicine. And she’s a medical student now. I was very surprised, but I’m very happy that she chose this career since I think that this is one of the most wonderful things that one can do – study medicine to help people that are sick.
I’m incredibly thankful to Prof. Hugues Abriel for taking the time to talk with me. I’m also grateful to Dr. Patricia Teixidor Monsell for the help.
Images by Hugues Abriel as well as by marcelkessler and Heidelbergerin from Pixabay