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Down the Rabbit Hole: Space Omics – Willian Abraham da Silveira

Willian Abraham da Silveira, Lecturer in Genetics and Genomics at Staffordshire University, joins us to discuss his work in the field of space omics – from his 2020 paper looking at the impact of spaceflight on mitochondria, to his involvement in NASA’s GeneLab platform.

Please note the transcript has been edited for brevity and clarity.

FLG: Hello everyone, and welcome to the latest “Down the Rabbit Hole” interview. Today, I’m joined by Willian da Silveira. He’s going to tell us all about the fascinating field of space omics. So, without further ado, Willian, could you introduce yourself and tell us a little bit about what you do?

Willian: Thanks for having me, it’s been a surprising pleasure to be involved in this event. I’m quite happy to be here today and to attend the Festival of Genomics & Biodata next January. I do a lot of things nowadays. I started as a pharmacist, and then I moved into transcriptomics to keep doing analysis. I worked as a bioinformatics analyst for three years in my postdoc. And at this point, I was working with literally everything. I was in the University of South Carolina at that point in the US, and their bioinformatics core. So basically, everything to do with bioinformatics passed through the core at one point and most of it passed through me.

Then one day, my boss knocked at my door and said, I received an email NASA – they’re trying to find some projects here in the States, would you be interested? And of course, I was! So, we set it up a small project and that was the beginning of my involvement with NASA. After that, we saw an advertisement from the project called GeneLab, so I tried to convince my boss to join (he didn’t need that much convincing) and we entered it. But he basically said, I’m too busy and this is your thing, do whatever you want and just keep doing your thing. So, that’s what I did. And of course, I kept doing my job as well – my PhD was in transcriptomics. I worked with more network biology and so on. But this is basically what led me to working in space omics today – because of that fateful knock on the door. And some strange decisions after that ended up pushing me to the GeneLab multi-omics analysis group. And then because of a lot of other things, and because of my involvement in the bioinformatics core and my strong biological background, I ended up being the guy who would connect the dots.

FLG: That’s an amazing story. I think that’s a great intro to how you got into this space. Obviously, space omics isn’t something you come across every day. Was it just pure chance that you got into that? Or were you interested in it before?

Willian: It was pure chance. I was not even aware of the existence of space omics before we entered that project. Because when you think “NASA” you think about rockets, satellites… it was not like I imagined they have anything to do with the biology related to keeping the astronauts alive. One thing that I have to be clear about is that I am Brazilian. I’m not from the US or the UK. I’ve lived there. And I’m living here now. But I’m not from here. And from my perspective, I never really thought I would work in space research. It was literally out of my reach in my mind. But it became a reality and I thought: Okay, let’s see how it goes.

FLG: Amazing. We’ll get into more detail about some of your research projects that are really interesting, but could you maybe give us a bit of a summary of some of the key areas that you’re working on at the moment?

Willian: Now, I’m working more on teaching – that’s a key part of the evolution of my career, the one point that I have to focus more. So I’m teaching a lot in genomics and bioinformatics, but there’s also some research I’m trying to build on from our 2020 paper. We did a multi-omics analysis of really a lot of data, different organs and different cell lines of astronauts to see what could be happening with the astronauts and we ended up seeing that a lot of things have to do with mitochondrial dysfunction. But there were a lot of stories that could not be told there, and that was our principal focus.

From there, I have been working on two things. First, to help to build a network on space omics in Europe itself. So this is the space omics topical team that is funded by ESA and I am co-head of the team. But more personally, I’ve been working with some students to follow through some of that work. So we just published a paper last month, to see the crosstalk between liver and muscles and to see how they could be interacting with each other. And we have only transcriptomics to work with , but we’ve been able to show that muscle wasting in space has a mitochondrial component that does not exist here on Earth. This has been shown before our work, this was discovered in 2004. But we do also know that the liver is one of the principal organs of metabolism in the whole body. So we’re trying to see how they interact, for example in diabetes. So we could find some correlation between genes.

And of course, the next big thing is to try to see if we can alter that. So I’m trying to find some collaborations and funding on that, to work on how to not only to see the problem but also how to solve the problem. So I’ll use this as a framework for my bigger research that is focused on network biology, how to understand how this is being altered, and discover a critical point that we could try to intervene to make this not to happen.

FLG: Yeah, there’s a lot to delve into. That’s brilliant. So, this goes back to the sort of basics, but just in case anybody out there isn’t sure. What is space omics?

Willian: Oh, yeah, I have not answered the basic question! First, you have the whole field of omics – transcriptomics, genomics, proteomics…And you can apply this to anything, you can apply it to diabetes, you can apply it to aging. But space omics is to apply our latest technologies to space biology on space. Why is this important? First, because we have a very limited number of experiments in astronauts that have ever gone to space. A very, very limited number, it’s very expensive. And with omics, we construct the maximum amount of information that we can from those samples, so we can increase the benefits, for example in terms of cost.

For you to have an idea, this whole paper we are talking about in Cell, we never sent anything to space, we simply used data that was already sent to space. And we’re the only ones to try to put it together at the same time. And we found something with that, that no one could have found before. And this by itself was really, really powerful. There are a lot of stories we could tell from the data, but we just told the strongest story we could find. What we hope from that is to be able to produce better data to support astronauts in the future, not only on the International Space Station, but NASA, ESA and other agencies building models on the moon – they’re trying to send people to Mars. And there’s one specific thing that makes this discovery quite important – travel to Mars and back can take up to three years. And we know that mitochondrial dysfunction kind of gets back to normal when the astronauts are back on Earth. This is what we could measure. But we also know that mitochondrial dysfunctions can act differently. And we don’t know exactly is how this could play out in space. But principally, the signals get stronger with time.

FLG: That’s really interesting. And so, these applications from your research don’t just apply to space travel. There are also applications back on Earth?

Willian: Yes, of course, I can think of two specific examples. But of course, I’m sure there will be more. When this paper got finally published, the first thing I did was to contact the (I think) Mitochondrial Disease Federation. Because there are rare diseases, rare mitochondrial diseases, that at this point, they have not many treatment options. And not much time in the spotlight. They’re quite rare. So I sent the paper to them, and we had a good meeting, with the idea of bringing more attention to the diseases. This is quite important – I would imagine that because it’s that rare, people will think oh, okay, that’s nice, but you know, it doesn’t change the word. But the thing is, everyone listening to this video will have (at one point) mitochondrial dysfunctions. Why? Because this is what happens as you get older.

As you get older, your metabolism starts to change, a lot of things change. And one of the things that changes is our mitochondria don’t work as well. This impacts a lot of things, for example, it increases your chance of type II diabetes, but also changes your metabolism and energy. And of course, if you cannot produce that much energy, then you die. I think I forgot to say, we can use Spaceflight as a model for accelerated aging. Because a lot of things that happen with astronauts makes it look like they’re aging really fast. They’re losing muscle mass, they’re losing bone density, a lot of other problems that could be related to that too, including vision and hearing. A lot of things happen with them. So if we manage to find something to help astronauts combat aging, it can be used directly to help us here on Earth. People are happy, we spend less money on health, the government spends less money on you. So it’s a win-win situation for everyone. So this is how this this research can be useful for all of us here.

FLG: Yeah, that’s really fascinating. It’s great to see how the research can be applied back on Earth. So yeah, you’ve we’ve kind of started talking about it, so I think we should just go straight into that 2020 paper a little bit more. This was about how spaceflight causes mitochondrial stress. I saw actually that it was recently cited over 100 times, so congratulations!

Willian: Thank you, I was quite happy, it is the first paper I have that’s reached that number of citations.

FLG: Amazing. We’ve kind of start talking about some of the applications already. But what research question were you trying to answer with this study?

Willian: That’s the thing that is quite difficult with omics research, it’s quite easy to get lost, if you don’t have a specific question to try to dig into with the data. So we started the analysis really broad. Our initial questions were more technical than biological. We had this huge amount of data (we can talk more about GeneLab in a moment) but we didn’t have a way to try to put all the data together and see how to build this to give an overall picture of what was happening. That was quite difficult. I had the honor of being the first author on the paper, but we’re seven coauthors and 38 scientists – lots of people were involved, and I’m quite proud and honored to be here talking to you about it.

So it was quite difficult in the beginning, because you know, everyone was doing one piece, everyone was focused on a different thing. And we needed to work out how we could put these pieces together. So that was the point where I could help – with my biological background, I proposed doing two things. First, not to try to integrate them on the gene level, because that will be really complicated, if you have different technologies, different things happening, that would make it really find difficult to find genes and all of the things that we do all the time. So we got out of that. We decided to integrate on the system level – what pathways are we seeing, and then we can go to genes after that.

The second decision was that because there was so much data from so many different technologies, it was really difficult to harmonize the whole thing. So we decided to analyze each data set as itself independently. And then we would try to integrate the results at the system level. We used GSEA (gene set enrichment analysis), a simple and powerful analysis that I really love. The visualization was done by a group in California but we used it across our group, everyone was using it. I was myself analyzing the liver, because as a biochemist you know if you’re trying to find something, I’m sure the liver will be involved in it, right? So I started to analyze the liver. And I remember, I had to do this in my free time. So I remember it was a Sunday, I had just finished the analysis and I thought that’s really strange. I just looked at the data like, what the hell? A liver in space looks like it has Type II diabetes? But when I eventually started to present the analysis (and mitochondria was always my favorite organelle) everything ended up being related to the mitochondria in the end.

And we had some different hypotheses of what could be going on there. Very strong hypotheses from very, very intelligent people. And then we had a talk about that, it was quite an intense talk, because of course, everyone was arguing their own hypotheses. But what was interesting for me was that one guy from a different group was presenting a result that he could not explain. And I started to laugh at that point, because I have pointed to exactly the same thing in my data. And I had thought if I found this missing data it would be a strong signal for what I was proposing. And then when he said this, I said, give me five minutes while I go add this in. But that was really nice, because it was totally independent of me. Someone did it in different way.

But the thing is that, you know, Occam’s razor – my hypothesis could explain their hypothesis, but their hypothesis could not explain mine. So we ended up like, doing some other questions. And at that meeting, Chris Mason, who was quite involved on the Twin Study. I can talk more about that later. But they had two astronauts – if you are thinking about a proud family, this would be that family – both were astronauts, and one stayed on the space station for one year and one stayed here, and they could try to see what was different. And I remember we asked Chris whether he’d seen anything in the Twin Study (which had not been published yet) that pointed to mitochondria. And he said, Oh, yeah, all the time. I could have kissed the guy at that point. And that was when we decided, or we agreed on the mitochondria hypothesis – after that was two more years of a lot of work. Because of course, we could see totally different things happening. But there’s one core thing happening in our cells and organelles, which is that pathways related to mitochondria are altered. Some up some down. When we put mitochondria in the center, all the other things start to make sense.

FLG: Yeah, I mean, I think that’s fascinating. And like you say, it’s amazing with multi-omics, that you kind of come at it from so many different angles. I want to ask you a little bit more about that in a bit. But I think it’d be great, as you can you’ve alluded to them a little bit there, if you could tell us more about NASA’s GeneLab platform, and also the twin study.

Willian: GeneLab, for me, is one of the most important spatial biology tools we have now. And I don’t say that lightly. First, I will not be here talking to you, I would never have entered space research if not for GeneLab you know, we have like a small grant. But that small grant unfortunately, ended and we could not we change countries so that did not follow through. So we adjusted. But GeneLab is a repository of omics data that is publicly accessible across the whole world. That means that anyone right now, in any part of the world, could be a space scientist. Anyone, something that was not even a possibility five, six years ago. Of course, it is much more difficult if you want to send something to space. And we have a reviewer proposing that to us in a paper – I said politely that even if I got approval it was going to be seven to 10 years just waiting for that paper so it would not be possible. So, but the data is there. And the good thing about omics, as I said that there’s so many things happening, and this is why it’s so easy to get lost.

So we ended up seeing one thing there and we could explain a really important thing. But there are a lot of things we could not touch because it was not the point of the paper. And we are trying to touch on some of these now, but again, it is only when people with different backgrounds come together to look at things that these can be solve. So the possibility of space biology is really to get faster and bigger, and that’s all just because GeneLab exists, it is really great. And they’re wonderful people. They’re so nice, I like to hang out with them every time I can – like the people in the lab are quite nice.

They’ve recently formed working groups, originally for multi-omics, animals, microbes and plants. And after we finally published the mitochondrial paper. One good friend of mine, Richard Barker, he’s wonderful, wonderful guy from the plant group. He said you know, this is so basic that I was quite surprised I have not seen things like this in plants before. So he tried to see it in plants, and he could not. So what he did was take all the genes from plants, and usede the homologues for animals (the closest thing he could) and then? He found mitochondria all over the place. So that is a paper that can give rise to a lot of others I think. And this is the best kind of paper. I’m still amazed and afraid of this paper because I know it is a good thing. And I’m totally afraid I will never do something as good again!

FLG: I’m sure you will. I read it was the largest cohort of astronaut data for use in analysis. So I wanted to ask you, you mentioned a little bit about data integration and things like that, what challenges did that pose?

Willian: There were a lot of things at first, you know, because no one knows everything. That’s where we start. I am more of a transcriptomic guy than I am any other thing. So we can understand and interpret other things. But if you go to proteomics and metabolomics, oh my god, they’re two different beasts. But we have some good guys, they’re doing the microbiome and the, the proteome and the metabolomics, the epigenetic side. But we found less things on epigenetics, epigenetics is more difficult if you don’t have like a bigger group, and so on. And of course, if you look at three specific places, you will see different things. One alteration that’s quite important in the adrenal gland would probably not be that important in the eye, and so on. So that was something that was difficult because I had to argue a lot. And this is one of my strongest points on the group, as a health professional, and not as a computer scientist. Even if my analysis sometimes was not as refined as other people’s analysis, when the analysis was done, and the data was able to be interpreted, it was easier for me to make sense of the results and try to explain it in a better way. Because I could take other people’s analysis and put it in the context of what I found. And this was really complicated because again, a lot of data, we have to prioritize and see what to focus on because if not, we would really get lost. There are too many things happening. So the data integration was quite a problem. And we kind of just figured it out as we went, which is not necessarily the best way of doing it, but it’s how we could do it and it worked for us. So this is something that was Yeah, was difficult.

FLG: Did you have any tools available to you to help overcome these challenges? I think you mentioned before, like maybe a data visualization tool?

Willian: Yeah. So people in California, and I’m terrible for names, they did like a new visualization to like for networking. So other tools, they give you a really long table. It’s really difficult analyze this really long table. There are different ways of doing it. But yeah, there’s what they do. There’s different ways that you could try to put this together, but this team developed a new visualization tool that was able to put different data sets on the same analysis and different like bubbles of things, and the code linked to the different things. So this was quite useful for interpretation, because you could try to see the patterns happening where they were appearing and what datasets they were doing. Because our pathway is not being altered in all our organs or all our cells. You know? So you’d have to devote a lot of time trying to look at different clusters and see what was there. And so yeah, data visualization is a challenge because it could make life easier or it could make life more difficult.

FLG: Yeah, definitely. Could you tell us a little bit more about the Space Omics Topical team?

Willian: Oh, yeah, of course. So my involvement started with NASA when I was working in the USA. But sometime after that, I moved to Belfast, Northern Ireland. So I got away from the US go to Europe. There are things that NASA could not do for me, for example, NASA don’t send money away from the USA, so you can keep collaborating with them, but they don’t send the money away. So if I wanted to keep going in the field, I had to find ways to work more with other partners on this. So I was working with the GeneLab group just before the pandemic, we had one event, the biggest, the biggest space event. And I was invited by NASA to give a talk about our work. At that point, I thought okay, that’s it, I’m going to send an email to all the European researchers that I know, I’m going to try to have coffee with them, see what happens.

I was able to organize three or four meetings. And at one of these meetings we discussed founding a topical team? So this is how the head of the team and I started. So we have people from the UK from Spain, from France, from Germany, from Sweden from  Belgium and I’m probably forgetting some country here, but we have like a big group of people, initially just to talk with each other. We’re going to meet now in Madrid in December.

The final thing, we did our work during the pandemic, we just finished publishing a special edition on the European contribution to space omics science. And one of the flagships of the special edition was a review about what was done in Europe, on space omics, even when we found some members of the group as well doing that, but the whole, the whole idea of this work was okay, we need to know who is doing what, where, and who’s paying for it. So we’re able to get together a huge vision about it, including funding. For example, in the US, NASA pays for everything, but in Europe it is much more complicated. You have ESA and they have national space agencies all over the place, they talk with each other and sometimes they don’t. And our whole point here is that we are in a strategic position to do much more than we do – we have really good infrastructure, really good people, and a space agency in different countries that is trying to make space more accessible. So this is the time to put more investment in it. And we could do a lot of things.

First, by influence of the members of the group – not me, I’m not that big – but by the influence of the members of the group ESA put on their strategy omics and bioinformatics. It is still being developed but it’s more or less in the final steps of it. That going to be part of the strategy. The other thing is that there will now be a network of projects between industry, academia and ESA that will also provide funding to develop biological projects in space, it won’t be purely omics but I’m sure that will be a huge part of that.

FLG: That sounds like a fascinating project. Are there any emerging research areas that you’re particularly excited about?

Willian: Oh, yes, of course. I’m quite interested in following through on our 2020 paper, so using omics integration, we saw a pattern that seems to be related to omics to mitochondrial dysfunction. But we never planned to test it, we just analysed the data. But we do have a lot of older papers supporting our view. But no one ever tested by itself. Last year there was training at NASA, and one of the directors was presenting things. And then he presented my paper! And then he showed some older papers, older papers of his, where mitochondria was there on the top, and he never really bothered to look, because he was thinking about different things. So we really have to go and see how strong and where exactly is this mitochondria from?

Another thing is that if mitochondria is our thread, I’m really interested to see what’s happening with chloroplasts. Because they’re not that different. There’s a some companies that have reached out to try say, Okay, if mitochondria is a problem, why we don’t give something to the astronauts to fight it. And it’s not that simple, of course. But that’s something that I’m really interested to follow through too. Again, because mitochondrial is one of the critical things related to aging and aging is something that interests me a lot as a concept. I am I’m trying to make the bridge between how much I’m doing with space biology now, to also be an aging researcher. This is really where I want to focus my career in the future.

FLG: You’re going to be speaking at the Festival of Genomics & Biodata in January. Could you tell us a little about what you’re going to be speaking about, but also why you’re looking forward to the festival?

Willian: Okay, so I’m going to talk there a little bit about what we have discussed today, you know, of course, I have to cite what I’ve done. But how we can try to focus this research on drug development. And I never really forget my routes, the pharmacist in me. I remember one of my supervisors said to me, you can tell you’re a pharmacists, you’re analysis really shows it. Because I’m trying to find a place where we could alter or try to change something, not only the thing by itself. So I’m going to focus a little more on that.

But my hope for the Festival is just to make more connections. I’m still new in the UK, you know, I moved to the US in 2019, just a little before the pandemic. And that was complicated. And then I moved here to England last year. So I really have to do my research as an independent researcher. So I want to do networking, meet possible new partners. And again, I’m really amazed by how the UK have the potential to do more. Of course, I want to be part of the guys doing more, and this is what excited me because there’s already something happening, but not as much as it could. So I want to bring attention to people and basically say, if you put money in it, you will get money out of it. Just give us a chance. You know, let’s be part of this too.

FLG: That’s all we’ve got time for today. But it’s been really great chatting to you. I’ve learned so much about space omics I did not know before. So I’d just like to say thank you so much for taking the time to answer these questions

Willian: It was quite a pleasure Lauren. I hope the people watching will like it too.

*Willian will be speaking about his work on using space omics in drug discovery at The Festival of Genomics & Biodata 2023. To see the full agenda and register for a ticket, head to our website.