Gabriele Lignani - interview - gene therapy
Video version of the interview available here.
Introduction
Torie Robinson: Dr. Gabriele Lignani! Tell us about yourself. What do you do?!
Gabriele: Thanks, Torie, for the invitation, first of all. I am a scientist and a researcher at University College London. The focus of my lab is working on finding new treatments for epilepsy, both genetic and acquired epilepsy. As for my background, I am a biotechnologist. I studied in Milan Biotechnology, and then I did a master's in Vienna, both in Italy, on Medical Biotechnology. Then I did also my Ph.D. in Experimental Neuroscience in Italy. I was studying mostly the part of the physiology mechanism of the rare mutations that cause epilepsy and autism. After that period, I decided to move abroad and try to use my skills in Molecular Cell Renewal Science, to try to do some more translational research, and try to find a new treatment for epilepsy.
Torie: One sec: what does translational research mean?
Gabriele: It means that the aim of that research is to find a treatment that can go to the clinic and help patients, basically.
Torie: Okay, well, that is the best kind because that is what we want, right?! Do carry on. Please continue. You managed to make it over to this island in the UK, then?
Gabriele: Before, I was studying more basic science, more on how things were working in the brain. Then when I moved to the UK, I joined the Department of Clinical Experimental Neuroscience at UCL. There were three people that were working on a new treatment for epilepsy. They were Professor Dimitri Kullman, Stephanie Schorge, and Matthew Walker. Basically, I joined their program on developing a Gene Therapy tool for epilepsy.
Gene therapy
Torie: What is Gene Therapy?
Gabriele: Gene Therapy means that it is a therapy that can change the genome, the DNA of the cells, and with that, you can treat the pathology and the rescue pathology in patients.
Torie: Loads of people freak out when we say, "Oh my gosh. You are going to mutilate our genes or something!", but I hope you can tell us why it is not like that and why it is not scary. Right?
Gabriele: No. No, it is not scary. Actually, I will explain it later, but we are doing the kind of Gene Therapy that does not create weird things in the DNA on the genome. Usually, anyway, the Gene Therapy is done in a way that if you have a mutation or something wrong in your DNA that leads to a pathology, we can correct them back to the normal DNA and rescue the pathology, basically.
Torie: Can you also explain to everybody because not everybody knows what pathology means?
Gabriele: Yeah. Pathology is a disease that has several causes and then can lead to a non-physiological functioning part of the body. It can be the brain, heart, or lungs it can be linked to.
Torie: You are focusing on the pathology of the brain?
Gabriele: Yes. Exactly. Mostly epilepsy.
Getting into epilepsy research
Torie: How did you get into epilepsy, though? Why did you make that kind of jump? As you mentioned briefly, it was not your specific “thing” in the beginning.
Gabriele: No. My specific thing was more biotechnology, modifying the DNA. During my master's at the university, I had a brilliant lecture about electrophysiology (it means the study of the electrical signal and how the neurons communicate with each other, basically) and I was fascinated about how the neurons communicate with each other and so I decided to do a project thesis in my master's, in a laboratory where they were working on how the neurons communicate with each other, but also how this communication is altered in epilepsy. So, I started working on epilepsy and I started to be more interested in that. After my thesis of master's and Ph.D. on studying the mechanism of epilepsy, I thought it would be a nice step forward to trials, to use this knowledge and find new treatment, basically.
Torie: That is certainly nice for us, as well, so thank you for making that decision. Then what happens? Tell us the next step.
Gabriele: The next step, I arrived in the UK. I started to work in this program. Then, I managed to find a new way to do this treatment and new approaches. I got a fellowship from Epilepsy Research UK to actually develop a new and very innovative approach for acquired Temporal Lobe Epilepsy,. At the moment, we are finishing the project but we already received investment for the next step. The next step is to go to the clinic. We have to do a lot of tests before going to the clinic to be sure that it is safe for the patients and that there are no side effects, but we have this idea that in two or three years, we should start the first clinical trial with this approach.
Torie: Okay. This is really cool because first of all, selfishly yes, because I have Temporal Lobe Epilepsy. Temporal Lobe Epilepsy, of course, is one of the most common types of epilepsy. Ever! I do not know. It is not like I read all the papers in the world. We have a lot of research understandably going into more specific, rarer types of epilepsy, which is wonderful, but we also need to have more generalised research into epilepsy that is very, very common, such as Temporal Lobe Epilepsy. I haven’t heard many people talking about this specific research though, that is why I am now getting tingles when you were talking about your research into that.
So when are you are going to the clinic to do “proper” testing on humans?
Gabriele: Yes. I have to say that the first clinical trial for Gene Therapy for epilepsy will start soon and is led by Stephanie Schorge, Matthew Walker, and Dimitri Kullmann. It is Gene Therapy for patients with focal epilepsy, that is of the temporal lobe but also other kinds of epilepsy.
In the first phase of the clinical trial, we will be testing the treatment in patients that can have surgery (where they (patients) have the focus of their epilepsy removed). Before that (the surgery), we shall test if the gene therapy works (for them) instead, and probably (have them) avoid the surgery. But if something went wrong (with the Gene Therapy), we still have the possibility to remove the piece of the brain.
In the lab
Torie: Yes. Cool. How are you coping with COVID, being trapped at home and everybody in your team working remotely? What is actually going on? How are you managing this?
Gabriele: Yes, it is not easy to manage it, obviously. I am at home because at the moment in our building, in our Institute, we have a policy of fifty percent of occupancy of the lab. There is a group of eight to ten people, so only four or five people every day can be there. I do not want to take space from people that work more on the bench and more experimental, so I stay home.
Torie: You are the guy that manages everybody really, right, because it is your lab.
Gabrielle: Yes, exactly, but we are doing well. They are really, really good. With half of the time available, they managed to continue the research that is not very easy at this moment. I am very happy with how they are dealing with that.
Torie: I am just imagining these guys in the lab right now because I have seen a couple of pictures of your lab, which you kindly sent me a month ago. But are they….they are not dissecting bits of the human brain. What do they actually do with the microscopes that you have got? How do you do it?
Gabriele: The microscope that you saw, we are using that to see the neurons that are not in the brain but are in a dish.
Torie: Okay. Petri dish, brain, simpler.
Gabriele: Exactly. We try on that to understand, as I was saying before, the communication between neurons and try to understand what went wrong when these neurons are sort of epileptic. We try our treatment to see if that can go back to normal levels. Basically, we are testing if our treatment can work.
Torie: Do you use computers and stuff a lot with that as well?
Gabriele: Yes!
Torie: It is not just about looking at this lovely petri dish? This is just me thinking of IVF where you see there is a sperm going around in the petri dish. It is not quite the same as that, right?!
Gabriele: No. Actually, the neurons that are in the dish are not moving, and the work we are doing is mostly electrophysiology; so studying the electric signal in which neurons communicate with each other. We use a very, very, very small glass pipette with which we touch the neurons and you can now record the electrical activity of the neurons, so you can understand how they communicate with each other. A microscope is needed to be able to see the neurons in the pipette.
Torie: That little pipette must be so tiny. I can only imagine how small that must be! So, do you go and poke one neuron, or do you poke a load all at once?
Gabriele: I think that pipette, more or less, is one micron (in diameter). That means a thousand times smaller than one millimetre.
Torie: That is amazing.
I am just thinking. I have got a little microscope over here and “Yeah, it’s got to be a little bit stronger than that!" This must take a lot of funding for this research? I know you mentioned you have got some funding for this - I am always saying that there is never enough funding for the research. Just you, telling us a tiny bit about it, and these are rather la-de-dah amazing microscopes you need. Then, of course, the cost of having the people of your team and paying yourself; this sounds like really top-of-the-range equipment and stuff you must be using.
Gabriele: Yes. Yes. It is a bit expensive research but is the only way to understand these things. There is not really any other way that you can understand the treatment for epilepsy, at least. You cannot work without these technologies.
Torie: Yes, it is so cool. I think it should be an encouraging thing for people who are thinking of possibly getting into mathematics, neuroscience, and anything within the sphere. I have spoken to a couple of mathematicians about epilepsy research. Well, I just did not use to think that mathematics is included, for instance, and I think loads of us have no idea, really, what you actually do there. It is like," Oh my goodness. You are so intimidating because you guys are so clever and you just do all this stuff that is going to go over our heads", which most of it, I must confess, certainly goes over my head(!), but it is really good that you just been able to say to us. Actually, this is the layman's terms explanation. "Yes. We are poking the neurons, and we're trying to find out this and that." It is really cool because this is what we need, the rest of the population. We need to understand those things, so I really appreciate that. What would you say are the obstacles in your work, in your research? What makes it tough? Bar the whole funding thing, of course, and bar COVID!
Gabriele: Yes. Obviously, funding and COVID are quite the major obstacles at the moment. One thing that I think that is very, very difficult in studying epilepsy is that it is very, very complex. I think that we need to know better some bases and mechanisms are the basis of epilepsy to understand better how to design proper therapies. I think that we are close to having a few therapies that I think could work, but I think that if we improve our knowledge on the mechanisms, I think that we will have more possibility to find the other treatment, maybe more efficient.
Torie: Well, I was actually going to ask you about prevention and stuff, as well, because we love treatments that work. A lot of us are not so keen on the side effects of treatment. What about prevention? Anything there?
Gabriele: Yes. It depends on the type of epilepsy. If it is a genetic epilepsy, something that changes the development of the brain, I think that any early diagnosis for example will be something that will help, for sure. Because if you understand the pathology that happens in development, you can understand from the beginning that there is something -you try to treat it (then) which it is better than when it is too late. I know that there are groups around the world that are working to improve the diagnostic. Also, speaking about mathematicians, mathematicians are also trying to create a model, to predict for example, if a certain change in DNA in a particular region of your DNA can lead to a pathology or not. It is also difficult to say, "Okay, we can treat the patient before seeing symptoms of the pathology", but you need to be sure that this patient if you do not do anything will develop this pathology!
Torie: Because we do not want to receive treatment for something that would not happen anyway.
Gabriele: Yes. There are a lot of mathematicians that are helping to develop the tools to try to understand if that mutation, that change in DNA is something that could be potentially pathogenic.
Torie: I was talking to a cool geneticist the other day, Charlie Steward (and we will be doing an interview, too) and he was just showing me a tiny part of the gene and how that split up into other tiny parts, how each of those vary, and how they might or might not mutate! Then, you might have epigenetics mutation, or you might not, and you do not know what turns that piece of the DNA on or off and…I’m not saying it right (!)… it just went over my head and I just thought, "Wow, that is amazing." Because I speak to lots of people and I am sure I used to probably think this at some point: "Oh, we will put a load of money into this research, and then you will be able to look at all of our DNA really simply", and you will say "yes" or "no", "This is going to happen to me. No worries. Well, here is the prevention." Yes, it is not quite that simple.
Gabriele: No. It is very complicated. It is for that, that we need mathematicians.
Torie: Yes. What are other types of roles that people play in epilepsy research?
Gabriele: Obviously, there are the clinicians. Then there are biotechnologists like me or biologists to do a bit of basic science about the mechanism and trying to develop the treatment. We are trying to design the treatment. Then, obviously, there are behaviouralists that understand also the change of the level of behaviour. There are physicists, mathematicians, engineers, and there are a lot of different people!
Torie: Yes. You have people who are doing things like paperwork behind or filing. I think without people in the back, as well, you will need to organise things.
Gabriele: Yes. We have a lab-manager. We have all the administrative people that are dealing with all the paperwork and bureaucracy! In our department, I think there are around fifty scientists with a few technicians, lab-manager, three-four people from administrative staff, plus we are very linked with the clinicians and neurologists.
Torie: Do you speak at all to the epilepsy nurses?
Gabriele: Not personally, no. In my project at the moment, no, but in other projects, they are involved. To develop a new tool for diagnostic, you need to speak also with the nurse to understand, but yes, I do not really speak much with them.
Torie: I have got a couple of interviews that epilepsy nurses coming up. Yes. It is interesting to see how everyone links together. I think even if you do not work directly together at any one point, their profession and behaviour and the data, they provide, impact your work and vice versa. Right? I think it is really important for us to see this broader picture.
Gabriele: Yes, actually, we speak with the clinicians, clinicians speak with nurses, so the clinicians are in the middle.
The next 5 years
Torie: Great! Lucky people! What do the next five years hold for you, your lab, and for us that are affected by epilepsy?
Gabriele: In the first next five years, there can happen a lot of things. First of all, we will have the first gene therapy trials of epilepsy so we will see how it goes. Also, we have a few other treatments that I think will be finished, be tested and so, probably, we will start other clinical trials. I think the next five years will be a very, very, big step forward for the treatment of epilepsy and I am very positive and optimistic!
Torie: You are! But that is what we need! Because for loads of us, as you know, life can be pretty pants at times, so it can be very easy to fall down into that black hole. That is why it is lovely for people to hear about work that you are doing that will positively impact so many of us, even if it does not impact me directly, just knowing that you are doing this, and that it is bettering the lives of so many people and not just people with epilepsy. We never know, the evidence from your studies, how that is going to benefit random others, right? I think that is what is really cool about neuroscience and research, as well. We just do not know! It is that unexpected thought of part of it. Do you know what I mean?
Gabriele: Yes. What we are doing is trying to find treatment or therapies for a broad range of people with several different kinds of epilepsy. We try to find, really, something that is a game-changer for patients.
Torie: What should people do if they want to find out more about your work? I know you have a cool website and stuff, but I often speak to people who might be interested in actually helping with research, if they can. I know it is not like we are going to go to your lab or something. What should people do if they want to learn more about you if they are interested?
Gabriele: If they want to put in the glass pipette…
Torie: Ahhh, yes, I would love to do that! But I’m so clumsy!
What should people do?
Gabriele: Obviously, they can contact us on the website. If they can, we organise seminars on experimental epilepsy where we discuss more on new potential treatments and new understandings of the mechanisms if that’s something that people are interested in – you can find that on my website as well.
Torie: I think on YouTube, as well. I cannot remember.
Gabriele: Yes. Every time that we do one of these, it would be on YouTube after.
Torie: I can say, personally, they are so cool, but I am like, "Oh my God. I feel like I need a scientific and medical-physiological glossary in front of me the whole time, and time to look up."
Gabriele: I know sometimes it is very, very, very, scientific because it is more for the experimental epilepsy community to be able, at this moment, to be together. Usually, we meet around the world at congress and conferences, but now, obviously, we cannot travel. The basis and one of the most important things in research is to be in contact with other people, to show the results to other people, to listen to the results of other people. With that, you can create new ideas and go forward.
Torie: You do work that compliments each other, without duplication - because what a waste of money and time that would be! Actually, that is what you said to me before – the work that you were doing in Italy - I think that you said that you were still working with these people in this other lab or something like that?
Gabriele: Yes. It was a lab that I was collaborating with when I was doing my Ph.D. and when I moved to the UK, I continued this collaboration. We are still collaborating and now, it will be more or less than 10 years that we are working together. I have collaboration, also, with other people because I think that, obviously, I cannot do everything! If I want to do something that will really make a change and that can be something very useful, I need also expertise from other people. Also, speaking and listening to people at congresses and seminars is very useful because when we listen we say "Ah. These things can be very useful for what we want to test." You can contact them and start a collaboration with them. I think it is very important.
Torie: That is so exciting. There are some prominent people certainly. Often when you mention someone, I’m like “Oh, yes, I know about that person and I know about that person!”. It is lovely to meet and speak with people. It is not just about influence, but it is about people, like yourself, who actually care and want to make a positive change. It’s not just about getting out your la-de-dah microscope and with your pokey thing and just saying, "Oh, this is exciting", just knowing that later that is going to help people. Maybe in the future, people will not have to have this dodgy bit of their brain removed. You can just provide some sort of treatment.
Gabriele: That is what we are trying to do, just to be able to not have surgery and be able to decrease your epileptic seizures without having that dodgy piece of brain removed!
Torie: Yes, and then not having the negative impact of that dodgy bit on your mental health, on things physically, and then being able to reduce your level of anti-convulsant drug. That would be so cool, as well.
All right. Perfect. Well, thank you so, so much. Also, for everyone, Rare Revolution magazine is featuring this marvelous chap, Gabriele Lignani in October. Rare Revolution deals with rare diseases and one of the things that, also, Gabriele is studying, is Dravet Syndrome, which is rare epilepsy (well, epilepsy is one of the parts of Dravet, anyway).
Keep your eyes out for Rare Revolution! We are also going to, soon, have Gabriele on the podcast, as you know is imminently going to be launched. If you know anybody who is not a video person, but they will put on their earphones whilst they are doing their washing or whatever and listen to our podcast. You can hear all about Gabriele there, as well. Thank you for listening and for watching us. Cheers, Gabriele.
Gabriele: Good night. Thanks, Torie.
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Torie Robinson
Keynote Speaker, Podcaster, Epilepsy Sparks CEO, Editor, Writer, et al.
*A pseudonym