ABSTRACT

First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping early-career researchers promote themselves alongside their papers. David Gurevich and Kathryn French are co-first authors on ‘Live imaging the foreign body response in zebrafish reveals how dampening inflammation reduces fibrosis’, published in JCS. David is an EBI Early Career Fellow with a lab at the School of Biochemistry, University of Bristol, UK, investigating the roles of inflammation and angiogenesis in tissue repair. Kathryn is an Academic Clinical Fellow in Oral Surgery in the lab of Prof. Paul Martin at the University of Bristol, UK, investigating wound healing, cancer, the foreign body reaction and scarring.

David Gurevich

Kathryn French

How would you explain the main findings of your paper in lay terms?

DG and KF: We all know of family and friends that have had some kind of biomaterial implant, whether it be a replacement hip, tooth or even a suture to hold tissue together – these sorts of procedures are becoming increasingly common and necessary in our ageing population. However, the way that these implants interact with tissue dictates whether they successfully integrate or fail and are rejected. This process, known as the foreign body response (FBR), comprises chronic inflammation, altered vascular supply, excessive scarring and the formation of foreign body giant cells. Although these general aspects have been well characterised in the clinic as well as in previous investigations on mammalian models, these set-ups prevented live imaging and are all performed on fixed tissue, limiting mechanistic insight into the dynamics of these processes. Using fluorescent transgenic lines marking immune cells and blood vessels, the optical tractability of the zebrafish model allowed us to visualise these processes, showing that many aspects of inflammation and angiogenesis issues associated with FBR are conserved between zebrafish and humans. Importantly, we were able to follow the same animals throughout the FBR process, identifying and comparing the dynamics of tissue inflammation, the formation of the avascular zone, and the behaviour of immune cells as they interact with two different suture materials that elicit different tissue biocompatibility responses. As an example of the mechanistic insight provided by these live imaging studies, we were also able to capture the macrophage fusion events underlying the formation of foreign body giant cells, the first time such events have been imaged. Our studies also revealed that dampening inflammation through genetic or chemical means is key to improving integration of even highly bioreactive suture materials, by reducing fibrosis and avascularity surrounding the suture. Overall, we have established the zebrafish as a powerful platform to further study FBR and screen for combinations of factors and materials that modulate its severity.

Were there any specific challenges associated with this project? If so, how did you overcome them?

DG: Most of my previous work has been studying wound healing in larval zebrafish, so I know my way around fish and small manipulations. That being said, it was quite the learning curve performing suturing of very fine gauge sutures on scaly, rubbery adult fish – microsurgery is surprisingly tough, and made me have a far greater appreciation for the sheer hand-eye co-ordination and skill involved in Kathryn's day-to-day job!

KF: Combining clinical work and basic science is always difficult and I left towards the end of the project to go on maternity leave in America. Though it was a challenge in the zebrafish, I really enjoyed the hands-on aspect of suturing under the microscope. It gave me an excuse to hone my microsurgical skills and it was nice to be able to pass those skills onto David after he had taught me so much about zebrafish husbandry and imaging.

When doing the research, did you have a particular result or ‘eureka’ moment that has stuck with you?

DG: I think sitting in front of the microscope and seeing our first foreign body giant cell, knowing that they were occurring in the fish and we were actually going to be able to image them got us both out of our seats, lots of high fiving that day! The set of experiments where we showed that hydrocortisone treatment to suppress inflammation drastically reduced avascularity, fibrosis and foreign body giant cell formation was less ‘eureka’, but was a very clear cut and satisfying result that really confirmed to us the value of this research.

KF: As David has mentioned, the moment we could confirm the fusion of macrophages to form multinucleate giant cells in the fish was great. It was something we'd been told was lacking in the zebrafish model and it was amazing to see it happening in real time.

Why did you choose Journal of Cell Science for your paper?

DG: Serendipity. We had this manuscript ready, but weren't sure where to send it – the somewhat clinical emphasis of our first draft meant it wasn't a natural fit for many journals. Then we heard that JCS was doing a Special Issue on the immune cell and inflammation. We made some tweaks to the manuscript to really focus on the basic science and immune cell aspects, and the rest is history.

KF: I had to leave the submission process down to David as my son was only weeks old; however, JCS has always been a go-to journal for basic science interests since my undergraduate biological sciences degree.

Two frames from a timecourse of double transgenic Tg(mpeg:mCherry); Tg(tnfα:GFP) larvae. This image shows for the first time the process of macrophage fusion in vivo, forming a foreign body giant cell in response to persistent inflammatory stimulus. tnfα:GFP-positive cells fuse with a number of tnfα:GFP-negative macrophages and their GFP becomes diluted throughout the newly fused cell.

Two frames from a timecourse of double transgenic Tg(mpeg:mCherry); Tg(tnfα:GFP) larvae. This image shows for the first time the process of macrophage fusion in vivo, forming a foreign body giant cell in response to persistent inflammatory stimulus. tnfα:GFP-positive cells fuse with a number of tnfα:GFP-negative macrophages and their GFP becomes diluted throughout the newly fused cell.

Have you had any significant mentors who have helped you beyond supervision in the lab? How was their guidance special?

DG: My most significant mentor would have to be my postdoc supervisor, Prof. Paul Martin. From taking a chance on me straight out of my PhD (I was moving from Australia to the UK, and hadn't published anything out of my PhD yet, so it was a fair risk for him!), to helping me figure out how to write papers, grants, and understand how to ‘work’ a project over to maximise its impact, Paul has definitely had a huge role in how I've developed as a scientist.

KF: Prof. Martin has been a great support and guiding figure in transitioning from clinician to clinician-scientist. He has given so much time and many resources that made this project possible, and I now hope it will act as a springboard for future work. Prof. Steve Thomas is an oral and maxillofacial surgeon and also a successful epidemiologist who has been hugely influential in my career. He works in Bristol and has helped nurture a whole generation of clinician-scientists within the dental hospital.

What motivated you to pursue a career in science, and what have been the most interesting moments on the path that led you to where you are now?

DG: Ever since I was a kid I've always liked figuring out how things work, which probably had something to do with the science and engineering books my parents were always buying me! So some kind of a career in STEM was on the cards, and when my mother got sick and subsequently passed away from cancer – I was 17 at the time, and deciding what I was going to do at university – the choice to do biomedical science was the obvious one for me.

KF: I completed my undergraduate biological sciences degree at the University of Oxford, but strayed away to the world of dentistry when I decided that I wanted a more clinical and patient-focused career. However, I always wanted to continue research and a trip to Prof. Martin's lab where they were using the zebrafish to look into the science behind wound healing and inflammation really peaked my interest. There were other clinicians working in the lab and I saw that a career combining both science and surgery was possible. I also met my husband (another surgeon) there! I was then lucky enough to secure one of the very few NIHR-funded academic oral surgery training posts in the UK. This has allowed me time alongside my training to pursue my academic interests.

Who are your role models in science? Why?

KF: Prof. David Thomas at Cardiff University combines a brilliant basic sciences laboratory with a surgical career and always has time to help and advise early-career researchers.

What's next for you?

DG: I'm putting together a few fellowship applications to start my own lab, focusing on compromised wounds (such as diabetic wounds) and ways to enhance their healing, most likely staying in the UK.

KF: Continuing my oral surgery training and applying for funding to complete a PhD in wound healing and scarring, utilizing the unique properties of the zebrafish and the wealth of genetic data we have in Bristol. I hope that combining all of these tools will result in discoveries that can help some of the patients with more complex cases that we treat in the dental hospital.

Tell us something interesting about yourself that wouldn't be on your CV

DG: Science is a pretty sedentary job, and failed experiments can be frustrating, so my favourite way of unwinding and staying active is heading down to the local strongman gym – and much like my science, I try to leave no stone unturned!

KF: When I was about 15 I held the Welsh Championship record for the discus!

David Gurevich and Kathryn French's contact details: Biomedical Sciences Building, University of Bristol, University Walk, Bristol BS8 1TD, UK.

*E-mail: david.gurevich@bristol.ac.uk; kathryn.french@bristol.ac.uk

Reference

Gurevich
,
D. B.
,
French
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K. E.
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Collin
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J. D.
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S. J.
and
Martin
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(
2020
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Live imaging the foreign body response in zebrafish reveals how dampening inflammation reduces fibrosis
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J. Cell Sci.
133
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jcs236075
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