Each year, the British Society for Developmental Biology (BSDB) awards the Beddington Medal to the best PhD thesis in developmental biology. This year’s award went to William Razzell, who completed his PhD in Paul Martin’s lab at the University of Bristol. At the BSDB Spring Meeting last month, Will presented his thesis studies of wound healing, in which he’d used Drosophila as a model. We caught up with Will after his talk to ask him more about his work, to find out what he’s doing now, and to ask him if he has any advice for PhD students.
Congratulations on winning the Beddington Medal. Can you tell us a bit more about your thesis work?
Thank you. I used the Drosophila embryo to model two aspects of wound healing. First, I looked at how innate immune cells are rapidly recruited to wounds in response to a hydrogen peroxide signal, which is made by an enzyme called DUOX. I found that calcium signals in the wounded epidermis, that it can kick start the wound inflammatory process by activating DUOX, and that removing DUOX’s ability to sense calcium prevents hydrogen peroxide release and recruitment of innate immune cells. The second aspect I studied is how epithelial wounds in the Drosophila embryo repair, as they close extremely rapidly and efficiently compared to mammalian adult skin wounds. This is because they close by assembling an actomyosin cable that contracts the wound edges together until actin protrusions extending from the wound margin interdigitate to seal the epithelial hole. We know that these wound edge actin machineries are important for wound closure, but we know less about how cells surrounding the wound contribute to wound repair. I looked at cell shape changes associated with wound closure in the Drosophila embryo and saw that the cells have to stretch towards the wound but also shrink their junctions with neighbours in a myosin-dependent manner. This is important for remodelling the epithelium surrounding the wound edge, allowing for cell intercalation events, so that the actin cable can efficiently pull the wound edges together. The same events occur during an earlier developmental event in the embryo to drive tissue elongation, consistent with the idea that cells at the wound edge can reactivate developmental pathways in order to close the wound.
Obviously there are lots of different models you could have used, but you chose Drosophila as a model for studying wound repair. Why?
Drosophila have two really big advantages. One is that they are genetically-tractable, which means that we can do very rapid genetic studies on the embryo, such as genetic screening or efficiently mutating genes with ever advancing tools including CRISPR technology. The other huge advantage is that you can live image embryos. For example, we can simultaneously label and follow different populations of cells during wound closure, such as the damaged epithelium as it closes and the innate immune cells as they migrate to wounds. This gives us the opportunity to observe cell behaviours that contribute to wound closure live in the embryo and analyse how these very dynamic events contribute to wound repair.
What can your studies tells us about wound healing in humans?
Through these sorts of studies we can identify genes or signalling pathways that are involved in wound closure that might be conserved during mammalian wound healing. We can also use live imaging studies in Drosophila to get clues about how cell behaviours may contribute to closure of human wounds, which we cannot yet live image. For example, the junctional rearrangements I observed in Drosophila wound repair may give us clues into the junctional changes that could be involved during the repair of human epithelial wounds.
And I guess, in the long term, the aim is to improve that process?
Of course! We would really like to improve and speed up the wound healing process. At the moment, there are a lot of people who have chronic wounds or suffer from impaired wound healing or excessive scarring – we want to be able to enhance wound repair in these patients.
You recently moved to New York. Can you tell us about the work that you are doing there now?
I joined Jennifer Zallen’s lab at the Sloan Kettering Institute in New York. I’m using the Drosophila embryo again, but I’m now looking at the earlier developmental event of germband extension, in which cells undergo intercalation events driven by polarised recruitment of myosin to cell junctions. I want to understand the signalling pathways leading to this myosin behaviour, and how this contributes to global tissue architecture.
Do you have any advice for PhD students?
One thing I found particularly helpful during my PhD is talking about my science to absolutely everyone. Visiting PIs, other PhD students…just anyone! I have shown my confocal movies to my parents, and although they are not scientists they can still look at them and see things that I can’t. You focus on the same things every day, and just showing your results to someone else can really open up your view. Giving presentations is also a great way to meet people and discuss your science with others. I didn’t do enough of this during my PhD but I think it is definitely something that can be a huge advantage to any PhD student.
Razzell, W., Wood, W., & Martin, P. (2014). Recapitulation of morphogenetic cell shape changes enables wound re-epithelialisation Development DOI: 10.1242/dev.107045