Podcast – International Frontotemporal Dementia Genomics Consortium

Voice Over:

Welcome to the Dementia Researcher podcast brought to you by dementiaresearcher.nihr.ac.uk, a network for early career researchers.

Megan Calvert-O’Hare:

Hello. The International Frontotemporal Dementia Genomics Consortium generates genomics data to further extend the understanding of frontotemporal dementia. Frontotemporal dementia, whilst uncommon, is the second most frequent primary neurodegenerative brain disease, after Alzheimer’s, in people over the age of 65. Neurodegeneration occurs in the frontal or temporal lobes or sometimes both. This leads to patients exhibiting progressive impairment of behaviour, cognition, and executive function and language. The characteristic impairments can make it difficult to clinically distinguish between FTD and Alzheimer’s disease at onset and during disease progression.

Megan Calvert-O’Hare:

This might be due to similar brain circuits being affected. But recent converging evidence has suggested a potential genetic overlap between FTD and other neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. This is where the wonderful work at the International Frontotemporal Dementia Genomics Consortium comes in. I’m very pleased to welcome two of the core team members here today to talk more about the research they are doing. Raffaele Ferrari, a junior research fellow at UCL in the Department of Neurodegenerative Disease, and Claudia Manzoni, an associate research fellow at the University of Reading, in the School of Pharmacy. Welcome to you both, [foreign language 00:01:30]

Dr Raffaele Ferrari:

Hi. Thank you.

Dr Claudia Manzoni:

Thank you.

Megan Calvert-O’Hare:

Let’s start with how you’re both involved with the IFDC. Claudia?

Dr Claudia Manzoni:

I am involved in the bioinformatic team of the IFDC and I help in taking care and processing the data sets. Additionally, I am in the admin team, and I help with the IFDC communications. So I curate the website, help with organizing these conferences and public events.

Megan Calvert-O’Hare:

Who funds your work?

Dr Claudia Manzoni:

I am employed on an MRC project grant that has been awarded to John Hardy, which is a professor at UCL and my direct supervisor, which is particularly at The University of Reading.

Megan Calvert-O’Hare:

Okay, great. Raff, could you tell us how you’re involved with the IFDC?

Dr Raffaele Ferrari:

Yes. At the moment, I’m involved multiple ways. I would say a one word fits all, in the sense of I’m kind of coordinating this international network. It’s a network made of 45 research groups all over the world. It includes North America, both U.S. and Canada. It includes, basically, the UK and the entire Continental Europe, and it also extends to Australia.

Dr Raffaele Ferrari:

The major focus at the moment has been collecting and generating genetic data for a vast amount of samples that we’ve collected thanks to this network. We basically now have up to 6,000 independent samples for which we have generated data. It’s probably the largest to date data set on sporadic frontotemporal dementia.

Megan Calvert-O’Hare:

Wow. It’s a large international effort.

Dr Raffaele Ferrari:

That’s correct.

Megan Calvert-O’Hare:

Could you maybe talk about some of the challenges that you’ve found along the way of trying coordinate everyone in the world?

Dr Raffaele Ferrari:

Lots of emails, lots of phone calls. We also get to meet once a year, which is great. Did you want to say something?

Dr Claudia Manzoni:

Yes. It’s just a very easy comparison. It’s like when you try to organise your Christmas dinner with your family, you have, I don’t know, maybe 10 people that you want to coordinate. And that is enough work. Imagine the coordination of 45 groups distributed all over the world. Different languages, different time zones, and different legislation, and bureaucratic procedures. It’s really a major effort.

Dr Raffaele Ferrari:

It could be depicted as a job by itself, whereas we do it in parallel with many other things we’re doing at the same time. I must say, “It’s challenging but it’s also a lot of fun.” You get to you get to speak to many people, you get involved in even different cultures to some extent. It makes it colourful. But the great thing is also about the contribution of all of these people. So ideas, creativity and also hard work because everybody’s then putting in a lot of effort and coordinating that is really rewarding.

Dr Raffaele Ferrari:

This has really taken off over the past two years. We’ve already used the data, we’ve generated multiple projects. We’ve published up to I think 16 manuscripts to date and all different sorts of projects, it’s not purely genetics. We’re moving to moving towards bioinformatics, and systems biology, which is an approach that allows us to go beyond genetics. So this far, genetics highlights genes, but that’s kind of where it stops. It doesn’t make the next step in trying to put them more into the context, especially into the functional context. That’s what one of the things we’re trying to do, trying to make sense of the genetics from a functional point of view so that we understand what goes wrong in the neurons or what goes wrong in the system that then increases the risk of individuals to develop the disease.

Megan Calvert-O’Hare:

To explore that a bit more, you said, “It’s not just genetics, as it were.” You’re also employing bioinformatic and multi-ethnic approaches. Could you talk a bit more about actually what approaches you’re using? Are you doing computational modelling, that sort of thing?

Dr Raffaele Ferrari:

Yes. I’ll probably let Claudia speak more about this, but in a nutshell, what we’re doing is we’re using… It uses data which is already available, which other groups have generated in different compartments of the research community, with a difference that everybody has generated those data, say transcriptomics or proteomics data, metabolomics, et cetera. Although, we’ve not got to metabolomics yet. But it’s all these different groups or different topics that have been done separately and nobody ever talked to each other. What we’re trying to do is we’re trying to talk to all of these people to find ways to integrate the data to make more sense, because from the genetics to the functional translation, you need to walk through all of these areas, which are very informative.

Dr Raffaele Ferrari:

More practically speaking, what we’ve been developing is a number of pipelines which involve gene expression networks and protein-protein interaction networks. This is what we’ve been particularly developing with Claudia.

Dr Claudia Manzoni:

Again, I will go back to our simple example here. As a training, I am a cell biologist and a biochemists. When I started working here in the UK in 2010, I was working in the wet lab investigating autophagy and all of the involvement of the waste disposal in cellular models of Parkinson’s disease. However, I started to define two research questions. The first one is that if we look at complex disorders, such as dementia, we see that there are multiple genes that have been associated with the disorder. The fact is, that when we go in the wet lab, we study one gene at a time, maybe two genes, if we are lucky. My question is, can we find a way to have a look at all the genes that have been implicated in dementia altogether at the same time? Because if all these genes are associated with dementia, there should be one pathway or maybe few pathways that are actually communal.

Dr Raffaele Ferrari:

Or convergent.

Dr Claudia Manzoni:

Or convergent. Yes, of course. This is something that we cannot really do in the wet lab because it will be impossible from a technical point of view with the techniques that we have at the moment. But we can do this in silico between cause we can model it.

Dr Claudia Manzoni:

The second thing is that when we go to the wet lab and genetics is very good that I’m finding genes that are mutated. But genetics doesn’t tell you which is the function of that gene. As a cell biologist, I was given names, gene names from geneticists, and then I was left in the lab to try and see what was the function of the gene. That takes a lot of time, a lot of effort and a lot of data, and allies. The other question was like, “Can we find a way to give suggestions to the cell biologist, so that they can go to the wet lab and organise an experiment with some ideas and not just a fishing expedition?

Dr Raffaele Ferrari:

Trial and error.

Megan Calvert-O’Hare:

[crosstalk 00:09:58].

Dr Claudia Manzoni:

Yes. This is why then in 2014, I little by little stepped into system biology and bioinformatics to try and see whether we can use genetics as a starting point to model in silico all this pathway that then can be tested in the wet lab to rationalise a little bit more the wet lab work.

Dr Raffaele Ferrari:

Then I was coming from the other end, and you see that then we met. We actually realised it was the same question, but from the two different perspectives. I think this is also, in a way, it gives a better overview of the consortium itself. It involves people with different backgrounds, with multiple forms of expertise. We’re talking about clinicians, we’re talking about pathologists, we’re talking about geneticists, of course, bioinformaticians, cell biologists. Even more recently, we started talking to pharma companies because, of course, if you find something which could be a biomarker or a drug target, then you want to go to the next step and validate what you find, which is still a potential. It is really a sort of 360 degrees approach, where you take the input of everyone to make sense of the whole picture.

Dr Claudia Manzoni:

Also, because when you step in the world of computer modelling and making prediction or assimilation’s, you also need some statisticians and some mathematicians onboard. This is an expertise that is not my expertise and I think is neither your expertise. This is why we need a consortium because we need multiple people with multiple experiences and expertise. We bring them together, and together we will be able to produce and define pipelines.

Dr Raffaele Ferrari:

It’s an integration of expertise, so to speak.

Dr Claudia Manzoni:

Yes, exactly.

Megan Calvert-O’Hare:

We’ve talked with other research groups about how research is evolving away from single author papers and that one person working in a lab effort to, like you say, involving people with different skills because why do the steps yourself if you’re not a statistician. Involve other people. So this is a huge effort in that way. You have created a consortium of experts from around the world to answer important questions about FTD.

Dr Raffaele Ferrari:

It could work. It’s a format that can work for any disease. In fact, similar things are happening for Alzheimer’s disease. I’m sure at some point, all of these groups, which now looking in this sort of format at one disease, will also merge at the latest stage.

Megan Calvert-O’Hare:

I did want mentioned actually about co-morbidities, because you talked about different genes being involved in one disease, but there are different diseases involved in one person. Do you look at co-morbidities? Is that not actually how far you go with your genetic research or through research?

Dr Raffaele Ferrari:

One example is have frontotemporal dementia and amyotrophic lateral sclerosis, there’s definitely more than a gene involved, as in there’s more than genetics. There’s pathology, there is some clinical symptoms which are overlapping or seen in both types of patients. There’s definitely a number of things that go from the clinics down to the molecular biology which are the same or very similar. Then of course, there’s other factors, so called modifiers, that then determine whether a patient will develop more the ALS Syndrome or the FTD, be it the behavioural or the language variant. This is another strong point I think of consortia because some of these people who have an interest in frontotemporal dementia, at the same time have, probably, the possibility to see other patients with one of these commodities. So we can transfer the knowledge that we’re creating within the FTD arena further to these other diseases and then we can get feedback from them.

Dr Raffaele Ferrari:

What one of the things that we’re also developing is collaborations with actual groups who do similar type of job that we do with this consortium in ametropia lateral sclerosis, especially because of this link that there is between the two diseases. Definitely there is communication and we see that there is a link. So we’re trying to further increase the resolution at which we can highlight this link.

Dr Raffaele Ferrari:

Also, the differences because then that is important to when you get to the stage we want to treat a patient. Something that will work for one group of patients might work but not as much in the other group. You will need to add something, some adjuvants in one case, and some others in the other case. Then you still will have that common bit that you know you will be able to target and it will be of benefit to both of the patient groups, basically.

Megan Calvert-O’Hare:

I guess doing it that way, you’re, in a way, cutting out the phase clinical trial that involves giving a drug to a set of patients where you realise afterwards, “Oh, it was never going to work in them because they had this…”

Dr Raffaele Ferrari:

Modifier that makes this treatment ineffective.

Megan Calvert-O’Hare:

Yeah. By doing this work beforehand, it’s prep work for a future drug trial or something.

Dr Raffaele Ferrari:

Right.

Megan Calvert-O’Hare:

It’s separating outpatient groups who will benefit from certain things.

Dr Raffaele Ferrari:

Actually, you’re raising a point which is very important for two reasons, I think. One is, and that’s something that we’ve seen at the moment… We’re currently working on a particular project that added a layer of understanding. There is an element, which is the immune system, which has been consistently indicated as a risk factor in neurodegenerative conditions. It’s the case of Alzheimer’s disease, it’s the case of Parkinson’s disease, it’s the case of frontotemporal dementia.

Dr Raffaele Ferrari:

Thanks to the consortium, actually, this was a work led by other people within the consortium. So you see ideas and then you have the freedom to use the data to pursue a particular question. This particular project indicated there is, in fact, a pleiotropy, which means shared genetic areas that have a similar influence on two, yet different, phenotype s. What I’m saying, we saw a genetic overlap between frontotemporal dementia and autoimmune disease. The current work we are doing allowed us to look into this further. We now have at least a number of area of the genome, which seemed to be involved in both comorbidities. Also, we’re starting seeing elements within the immune system that could be targeted.

Dr Raffaele Ferrari:

It would be probably too optimistic, but I would start including the word “therapy.” Why? Because we know that these elements, that are communal to autoimmune disease and frontotemporal dementia, have already been evaluated in autoimmune disorders as potential drug targets. If the effect, which in this case is an uncontrolled inflammatory response… So what happens in the body is that the body itself, the immune system itself, is not able to balance the immune response. This could cause, based on where it happens, a detrimental effect. If it happens in the brain and it’s not modulated properly, it can cause damage to the brain itself.

Dr Raffaele Ferrari:

There are apparently some drugs which have been explored in autoimmune disorders that target a number of elements that we see altered also in frontotemporal dementia. If those drugs work in the context of autoimmune disease, they become probably the first targets that we would want to explore also in frontotemporal dementia. Of course, you might need to modulate that a little bit, but you already would have a target. From another disorder, you can transfer now, knowledge that you generate and you overlap with/or from other fields. And you could apply it to your own field or to your own disease that you’re looking at. You would never thought of it before.

Megan Calvert-O’Hare:

That’s the fascinating thing. In a way, all of these ideas are already out there, but you have to bring them together. In a way, it feels like science at the moment is getting to that place where they’re like, “Actually maybe we should talk to each other and we’ve all got interesting ideas and maybe they do overlap and diseases aren’t separate from each other. They’re all within our body, so they’re all affecting each other, potentially.”

Dr Raffaele Ferrari:

You can find shortcuts that actually you would never have thought of or it would have taken you 50 years to get there because you were actually going the other way.

Megan Calvert-O’Hare:

Yeah, somebody’s already done it.

Dr Raffaele Ferrari:

If you went this way, you would have met your answer already.

Dr Claudia Manzoni:

But you need to talk. This is a very good point. This is another challenge I think that we face within the consortium and with these large projects is because you need a lot of skills, different skills, coming together. People from different expertise, they don’t use the same language, so you really need to talk and to explain and to get used to the way the other people talk. It’s really a long process of understanding, and getting to know each other, and start to work together because people in different fields, they may not know which are the needs of people in other fields. You really need to work your way through the project together. This is something that we got to learn little by little with the consortium, I think.

Megan Calvert-O’Hare:

I actually wanted to go back to something that you’ve both touched on a little bit, is that you have your academic careers, but you’re also helping to run the consortium.

Dr Raffaele Ferrari:

Yes. It probably goes all together in a way.

Megan Calvert-O’Hare:

Yeah. But do you think you’ve had to learn management skills along the way that you’d know from your academic background you didn’t necessarily come with into this?

Dr Claudia Manzoni:

Oh, sure. Again, a very simple example, but we have organised now two meetings. Both of them were one day long. We had to invite speakers and organize the catering and booking the room and do a lot of admin things that nobody really tell you. Even involving pharma companies, and sponsors. Booking the room and checking that all the technical equipment was working.

Dr Raffaele Ferrari:

When you think about all those small details that you need to go through to make sure that the day, I wouldn’t say it’s going to turn out perfect, but it’s going to turn out decent.

Megan Calvert-O’Hare:

Yeah. I used to work for a medical communications company and we specialised in running symposium and conferences because it’s such a large undertaking and people then outsource it to you because it’s just easier.

Dr Claudia Manzoni:

You don’t understand the actual involvement, the effort in organising an event. If you don’t try to organise the event yourself, then when you start doing it, you realise that you really need a lot of skills and time.

Megan Calvert-O’Hare:

Yeah, time.

Dr Raffaele Ferrari:

It makes you grow 360 degrees as well. It’s professional. It’s personal growth as well, you get to learn, you get to speak with a lot of… You find yourself in situations you probably would not have put yourself if you didn’t have to. But then you figure out solving problems is fun. I keep on saying, it’s 660 degrees. It’s really 360 degrees. It’s a training at multiple levels. But then, of course, you need to deliver. You need to come back and you need to focus again on what your first priority.

Dr Raffaele Ferrari:

I still believe a first priority is that of understanding the disease. I’m applying it to frontotemporal dementia, but generally speaking, what we’re doing as a service to the community, is to try to understand to help making life easier or… Curing is a big word, especially in these sort of complex disorders. But if we’re not trying to understand what goes wrong, very simplistically put, we don’t know where to put our hands on to try and fix it, first thing.

Dr Raffaele Ferrari:

Then if we understand what is going wrong, and then slowly we can fix it and at the same time we can take a step back, and see how it fits in the bigger picture. Then start thinking about ways to intervene early so that you don’t even get to the stage where you just need to fix something or you can prevent it.

Dr Raffaele Ferrari:

These two things, prevention, to understanding to prevent rather than cure. Of course, curing is the current… Many people are affected now, so they need an answer now. That is definitely one very important point. That is what is the short-term focus.

Dr Raffaele Ferrari:

What the long-term focus should be, and is, in fact, is that of using all of the knowledge we’re creating also to go back and try and see how we can apply this now to make sure that this problem doesn’t happen at all.

Dr Claudia Manzoni:

In other words, I think is, of course, the community, what they want is a cure or a way to diagnose the disease before we get to a stage of large brain involvement. To get to a cure and to get to a diagnostic measure, we need to fill a certain number of steps. We cannot jump from pure genetics directly to the cure, or directly to the diagnostic…

Dr Raffaele Ferrari:

To clinical trial, yeah.

Dr Claudia Manzoni:

Or to the diagnostic measure. We have a certain number of steps. We need to compact a certain amount of knowledge and we are trying to do that. We are trying to fill the gap between genetics and the bedside. It’s a lot of work because genetics is only able to name genes. Then we really need to find what’s behind those genes that are named.

Dr Raffaele Ferrari:

They point at things, but it’s not really telling you how they fit in the bigger picture. That’s why all of these other people need to be involved to get to the next stage. Again, if we are all in the same room, and start speaking about the issue, and everybody kicks in with their point of view, with their expertise, there is where you start becoming time effective. Speaking also of cost effective.

Dr Raffaele Ferrari:

Now, technology is really helpful, not only in data generation but also in data management, data analysis, data sharing, and those sort of things. It’s a better era to be in science. The technology really helps a lot in speeding up processes.

Dr Raffaele Ferrari:

Then of course, it needs the brains of people to not only speed the process up, but also make it sensible and realistic and all those sorts of ingredients that are needed to be successful in this path that we’re pursuing. I think this is the major point.

Dr Claudia Manzoni:

Goal.

Dr Raffaele Ferrari:

And goal. In fact, also if you think still 30 to 40 years ago, not everyone could go almost everywhere in the world. Is jumping on a plane and just go in for a couple of weeks somewhere which is on the other end of the globe. Now, technology, planes are more affordable, there are many more flights, et cetera. You can actually do some of those things more easily than in the past.

Dr Raffaele Ferrari:

Similarly, now with the technology that is available to scientists and the way to communicate that is so fast today. You can literally do many more things and leave your comfort zone, leave your area, and get to speak to people and experts.

Megan Calvert-O’Hare:

Yeah, the consortium seems like a logical step in the process, is that now we’ve got this technology and freedom to travel and all the things that actually bringing people together to talk about all their ideas, is now how we’re going to talk about science and move science forward.

Megan Calvert-O’Hare:

You talked about the cost benefit. I guess, also in a way, you’re stopping doubling up because that’s not cost effective for anyone. If you realise you’ve got three labs in the world doing exactly the same thing, do you also sort of talk about that, gaps and overlaps within the research?

Dr Claudia Manzoni:

Yes. It is one thing that we need to keep in mind with the consortium. The reason why we need a consortium for frontotemporal dementia, but actually for all the complex disorders, is that if we want to do genetics for the sporadic population, we really need to have large numbers. For example, in frontotemporal dementia, most of the people that are affected by frontotemporal dementia do not have a familiar history, so they are sporadic cases.

Dr Claudia Manzoni:

To study the genetic of sporadic cases, we need some mathematical models and some statistical approaches that require large number of patients, so large cohorts. The consortium is really cost effective because we can put together different groups so we can organise a very large cohort and do those analysis. Otherwise, single groups, they can put together smaller cohorts. The work will not be powerful enough to discover a lot of genetic findings. While, if we put everything together, we save a little bit of money, and we have a much powerful tool to then investigate the genetic of sporadic disorder. This is another way why consortia in complex disorders are actually a benefit.

Dr Raffaele Ferrari:

The point is not only about different expertise, as you mentioned, it’s also about delegating. If somebody is very good at a particular technique or a particular approach and we have a question that needs that sort of answer, that methodology to the get to the answer, that group or that person is the one who’s going to take the lead on that particular project. You, yourself, coordinating or just indicating that person A or B or group A or B could do this, you are speeding up process that otherwise you’d need to go back, study the methodology yourself, go through all of the pitfalls until you get to a refined pipeline and then do it yourself. At the same time, somebody already in the consortium or somebody who wants to collaborate with a consortium and has specific techniques and capabilities, they’re going to do it. And they’re going to come back with an answer.

Dr Claudia Manzoni:

That is another way to save money and save time. And to get to the end point quicker, which is actually our goal.

Dr Raffaele Ferrari:

In addition to that, again, it’s not only genetics. For example, when we’re talking about early diagnosis, you need biomarkers. One point is that of, again, liaising with people who do blood biomarkers. You can talk to them, you can design your experiment, you can split it. Some bits you do, some bits they do. The interpretation, if somebody is already expert in that area, you don’t need to stay up all night to try and make sense of your data. You can just talk to them because they’ve done it already so many times. Again, you cut time. It’s very time effective. It’s also you want to be able to talk to the experts to get a reasonable and sensible feedback to take that information forward.

Dr Raffaele Ferrari:

For example, if you are able to identify some promising, say blood biomarkers or fluid biomarkers. There’s other types of biomarkers, imaging biomarkers, et cetera. You liaise with these people. You’re going forward at such a speed that then allows you really to try and validate this. What that means is that you’re not only finding something which theoretically could work, but you already have the access to somebody who can validate that, being the pharma or being other groups, drug discovery centres at universities, as well as private. These are all groups that now are involved in the consortium as well. It’s very promising to have all of these sort of expertise together.

Megan Calvert-O’Hare:

That’s fascinating. It feels like it’s more of a community effort than ego driven science maybe was in the past where you wanted to get a single author paper and have the biomarker named after you and set up your own lab by yourself.

Dr Raffaele Ferrari:

[crosstalk 00:34:09].

Megan Calvert-O’Hare:

This has been so lovely to talk to both of you. Do you have any wise words for early career researchers in frontotemporal dementia or wishing to set up their own consortium?

Dr Raffaele Ferrari:

Everybody’s experience is different. What you bring to the table is your personal experience where you elaborate on it. For sure, you really need to be passionate about… You really want to solve it, or you really want to have the drive that brings you out of bed in the morning. Otherwise, it’s really painful. Probably, you need to be a little bit ambitious in the good sense because never forget what you’re doing is a service to the community. You’re actually in a lucky position to have access to knowledge, to have access to technology, et cetera., to use this for the benefit of all.

Dr Raffaele Ferrari:

If this is your approach, the feeling that you can help somebody, that at the end of the road, your work, your hours, sometimes it’s also working overnight, which is fine, if you get where you want to go, you’ll put everything in place to be able to do so. You need to keep in mind it’s going to be hard work. There are going to be times that it’s really hard work and you’ll ask yourself, “Why am I even doing this?”

Dr Raffaele Ferrari:

At the same time, you’ll see the goal at the end of the road. The step forward when you understand something is very rewarding by itself, just a feeling of understanding something. All of a sudden something makes sense. If you can apply this to life, to life science, and it helps somebody or it helps a large number of people, that people feel better, people can cope with some symptoms they’re having in a better way, then I think this is the biggest reward you can have. If you’re passionate about something like that, passionate about service to the community, and passionate about solving something, just getting to understand something better and making a step forward, then academia is really a good place to be in.

Dr Claudia Manzoni:

When I was at uni, one of my professor told me, “Be flexible.” I think that is a very good advice. Be flexible because, for example, what I do now on a daily basis is something that I didn’t study at uni because some of the techniques didn’t exist back then. I started as a cell biologist, as a biochemist, and now I’m moving to be a bioinformatician. I am an expert in system biology now. You need to find your research question, and then you need to be flexible on yourself in order to find the best way to approach the question and to answer the question. Be prepared to change. This is my suggestion.

Megan Calvert-O’Hare:

Good for life as well, I think. Thank you both very much for coming in. It would actually be great to have more discussions on some of the rarer forms of dementia. If you would like to join us for a podcast, please get in touch and please feel free to get in touch with us if you have any questions about what we’ve talked about today using the hashtag ECRDementia. Thank you.

Voice Over:

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