An interview with Guest Editor Heidi McBride Free

Heidi McBride

Let's start at the beginning – what first got you interested in science?

Well, I grew up on a farm, and I guess farming is a type of science: you start to think a lot about how plants grow and the mechanisms that control their growth. So, when I was taking science classes in high school, it really hit me – the beauty of chemistry and biochemistry and the conversion of materials. I found it really fascinating. When I got into McGill University for my undergrad, I didn't really understand that it was possible to be a scientist; I just didn't know anything about it. As a farmer, I thought I would go into medicine or veterinary science or something. But when I realized that my professors were doing experiments and learning new things, it became clear that's what I wanted to do. It's been a passion of mine ever since then.

And how did you become interested in studying mitochondria?

During my PhD, back in the early 90s, I worked on mitochondrial protein import pathways. But while I was doing my experiments on isolated rat heart mitochondria, doing pretty much the same experiment every day, I saw all these cool stories coming out on vesicle trafficking. The likes of Jim Rothman and Randy Schekman were publishing exciting papers on Rabs and SNARES and vesicle dynamics – learning such detailed mechanisms of how things are trafficked in the cell. But no one ever mentioned the mitochondria, which were such a dominant organelle in the cell, at least to me. At that time, people didn't really think about mitochondria as dynamic organelles. We didn't know about their biogenesis or how they divided. There were so many questions – the field was wide open – and it made me angry that mitochondria weren't part of the discussion. When I went on to do my postdoc, I couldn't work on mitochondrial dynamics because there were literally no labs studying it. So, I switched to studying intracellular trafficking with Merino Zerial at EMBL, learning the principles of membrane dynamics and membrane movement, and how tightly regulated everything is. While I was doing my postdoc, Jody Nunari, Minx Fuller and Janet Shaw were discovering all this cool stuff about mitochondrial fusion in Drosophila and yeast. I was just losing my mind to start my own lab and get working on this in the mammalian system. And so that's what I did! I've been in the mitochondria field ever since then.

What are your main research interests now and what are the key questions that your lab is trying to answer?

I think the questions haven't really changed for me over the last 25 years, which makes it sound like we've made zero progress! I know this obviously isn't true, but many of the key questions remain. Why and when do mitochondria fuse? Why and when do they divide? What does this have to do with cell fate transitions? What are the roles of mitochondria as signaling platforms? Along the way, we discovered that mitochondria can select their cargoes and eject them in vesicles – most of this is for degradation but we're starting to realize that there's a lot more signaling going on. We still need to understand how the cargoes are selected and how this integrates with signaling pathways and, for example, inflammation. Overlaid on top of these basic mechanisms is the physiology side of things, which is a field of research that's just exploding. But it's difficult to link the large-scale omics data sets that are being generated now back to the basic mechanisms. This is a challenge that we still have.

And obviously there are lots of links between the basic mechanisms of mitochondrial cell biology and disease – is this type of translational work also something that your lab is engaged in?

My approach has always been to start with the mechanisms and see where that takes us. Soon after we discovered the mitochondrial-derived vesicle pathway, we realized that Parkin and PINK1 (two proteins associated with Parkinson's disease) could regulate the pathway in different ways, and this led us into the Parkinson's field. So it wasn't that I was interested in studying the biology of Parkinson's – our research just took us there. Many labs start off trying to understand a disease and then drill into the mechanisms, but for me it's the other way around. But this means that there's a big part of my lab that's highly collaborative. For example, we have a large team grant that aims to investigate the role of inflammation in Parkinson's disease – a project that spans from basic mechanisms all the way to physiology and some translational work with patient samples. We have also been studying a SUMO ligase in the mitochondrial outer membrane and discovered that, when we knock it out, the knockout animals develop spontaneous hepatocellular carcinoma. So, we now have teams working on the liver and cancer. But again, it all starts from the mechanism – the projects take me in different directions, and I engage with collaborators when needed to try to push projects forward and across scales and disciplines.

And where, in your opinion, has the most progress in mitochondria field been made?

When the field of mitochondrial dynamics really began, back in the late 1990s and early 2000s, there were just a handful of us. I remember doing an interview and saying that it was my goal for the intracellular trafficking models to include mitochondria – that was all I was asking for. But I think that is definitely true now. So many more labs are thinking about mitochondria and there are so many talented, incredibly brilliant young investigators studying mitochondria from all angles. They're looking at metabolic wiring, different classes of mitochondria, mitochondrial DNA, mitochondria in the context of evolution – there's just an overwhelming amount of evidence to show how mitochondria are central to everything (and not just cell death or making ATP). The fields of contact site biology, lipidomics and metabolomics and have also highlighted important roles for mitochondria. Metabolism is complicated and has kept people away from mitochondria for a long time, but there's definitely a new appreciation of their importance.

What's most exciting in the field right now?

I actually think that the most exciting thing for me at this point in my career is watching the rise of the next generation. I can see that many of the dogmatic themes that we argued about for decades fall away when the next generation comes in and just runs with it, ignoring all the previous opinions and preconceptions about things. It really helps to challenge our understanding and move the field forward. It can sometimes take a decade for a new concept to be accepted and most of that decade is spent arguing with sceptics. But the new trainees entering the field just go with the concept and make a load of discoveries based on it. I'm also seeing that the current generation of researchers is embracing new technologies way better than we ever could; breaking technological barriers is what opens new fields. It's a really exciting time.

But my main note of caution is not to forget the basic mechanisms: there are still so many gaps in our knowledge and there's still so much left to learn about fundamental and basic mitochondrial cell biology. If we look at how mitochondria fuse, yes, we've identified the mitofusins and we know that lipids are involved in some way, but that's all we know. We don't really know how GTP hydrolysis drives fusion; we don't know the fundamental things that the old school cell biologist would rack us over the wrists with rulers for not knowing by now! These kinds of experiments provide so much insight into individual proteins, pathways and mechanisms, and it's these kinds of studies that lead us to therapeutic targets and targetable processes. And I think that's where journals like JCS come in.

Why did you accept the invitation to be a guest editor at JCS and what were you hoping to achieve in this role?

My aim was primarily to try to convince members of my field to pull away from the drop-down menus of the big journals and support grassroots, long-standing, historically respected journals that really care about scientists. JCS is such an amazing journal that, for me, feels like it's been there forever; many of the important papers I read as a trainee were published in JCS. But I feel like JCS and other community journals are being crushed by the mega profit-making journals and publishers, which just seem to proliferate and spit out new journals by the day. I think we must all make an effort to move away from this and support the journals that are run by scientists for the benefit of the community. I know that JCS and The Company of Biologists have so many initiatives that support scientists, such as FocalPlane, preLights, Travelling Fellowships, Meeting Grants and so on. What do other journals do for you except take your money?

I also think JCS is the perfect journal for studies that report on the many mechanisms that are missing in the mitochondrial field. I really wanted to encourage people to send their work there as I think it's not on their radar.

And how have you found the experience?

I knew coming into it that there would be challenges. For example, I knew that it would be hard to find reviewers, and this has definitely been the biggest challenge. I think that the COVID pandemic affected people's willingness to do things far more than we appreciate. Before COVID, people would review way more than they do now and they would be faster with it. But after COVID, I don't know what happened – people's attitudes changed. It's like everybody's just worn down. I understand it, I feel it too, but I think it's a real shame.

While not specific to my experience with JCS, the past few years I've felt a growing concern among scientists that the review process has become far too critical and demanding in every journal. I think there needs to be more kindness in helping people get their papers out and have their voice. Everything doesn't have to be perfect; there will be a next paper to clarify and expand things. There obviously has to be rigor, but maybe reviews could be simplified if reviewers would limit their criticism by sticking to the scope and questions addressed in the study, rather than making broad requests to generate a new mouse model or introduce new technologies that the reviewer likes but the authors may not have access to. We should focus more simply on whether or not the data are well controlled and consider alternative interpretations of the data. I applaud the emerging trend to include a final paragraph that acknowledges the limitations of a study – this might often help satisfy reviewers. I know it's difficult but it's something that, as a field, we have to deal with so that we can get our work out there and allow our talented trainees to move forward. Journal editors could also play a more decisive role in helping to limit what can seem like endless revisions to address every single point made by all reviewers. As reviewers get more demanding, papers can end up with eight main figures and 18 supplemental figures, and they will often have an important cell biological observation tucked away in supplemental figure 17 where no one will see it. Important findings can become lost as a footnote comment to a reviewer rather than shared as a unique and important finding in a journal like JCS.

But overall, I enjoyed the experience and learned a lot about the editing and publishing process. I was especially grateful to be working alongside Ana Garcia Saez whose expertise is complimentary to mine as she's a biophysicist, someone who really understands mitochondrial membranes and dynamics (read an interview with her at doi:10.1242/jcs.206961). Ana has been a great partner throughout the whole process and has taken on a lot of the workload and helped me in trying to shape the issue. It definitely was an eye-opening experience and I'm glad I did it because, as I said, I really want to highlight JCS as a home for mitochondrial stories.

Are there any broad themes that have emerged from the articles published within the special issue?

The issue presents a spectrum of topics across the field of mitochondrial cell biology, with primary articles from across the globe on topics such as mitochondrial quality control, contact sites, dynamics, import pathways, lipid homeostasis and signaling. These themes highlight the depth and excitement of the field, and in my opinion, underscore just how much we have left to learn. We also have some exciting perspective and opinion pieces, insightful review articles, and informative ‘Cell science at a glance’ posters, as well as interviews with two incredible early career scientists in our ‘Cell scientists to watch’ series.

Finally, what do you like to do for fun (when you're not thinking about mitochondria)?

Living in Canada, the best thing to do for fun, of course, is to get back into the country, spark a mighty campfire under the stars with a cold beer, surrounded by family and friends. That – and spending time with my wonderful son – is what I love to do the most.

Heidi was interviewed by Seema Grewal, Executive Editor of Journal of Cell Science. This piece has been edited and condensed with approval from the interviewee.