Y-ECCO Interview Corner: Fiona Powrie

 

Fiona Powrie © Thomas S. G. Farnetti

Did your family background influence your choice of career as a scientist?

My mother was a nurse, so in that regard there was an interest in medicine. A big factor was that my mother was chronically ill with lupus throughout my childhood. That got me interested in immunology – and a desire to understand how the immune system, which is normally so useful, can turn on us, causing disease.

What inspired you in your early career?

I found that making discoveries was really exciting, and science offered that opportunity. At school, I was quite good at science, and then I did a BSc in biochemistry, focussing on the biology side – as that offered the most opportunity to study the mechanisms. During my university course I became more interested in how you could apply science to advance human health. At that time, I became aware of Herman Waldmann’s work, using monoclonal antibodies to tolerise allografts in transplantation. I hadn’t really been thinking of doing a PhD, but I was interested in his work, and I wrote to him to see if he had a PhD available. At that time he didn’t, so I went into accountancy after my BSc. That move sort of came from my father, who was an accountant, and finance looked like a reasonable career, so although I was good at and interested in science, I was a bit of a generalist, and to be honest not too focussed on future careers – I was just having fun. I had imagined that finance would take me to interesting places – New York and so on – but that was not where I ended up doing audits. I soon realised that accountancy wasn’t the career for me, and I wanted to get back to biomedical research. So after a year I left accountancy training and set about looking for PhDs. I was very fortunate to find Don Mason, a wonderful scientist and person who was willing to give an enthusiastic student who had followed a slightly different course a chance. I ended up doing my PhD in his laboratory at the MRC Cellular Immunology Unit in Oxford.

For many people their PhD is quite a formative experience, and often a springboard for an entire career – was it like that for you?

Yes, very much so. Studying T cell subsets and understanding how they were different from each other, and how those functions impacted on the immune response, was fascinating. It was becoming clear that T cells were not just T cells, but that there were subsets that could be distinguished according to the cytokines they produced. That was the early stages of the cytokine biology field. My work was one of the earliest to identify the regulatory T cells that police the immune system. I had very early experiments in my PhD that were striking in terms of the function of regulatory T cells. We realised that this was a host mechanism to prevent excessive inflammation and control the immune response. I had been interested in how the immune response can turn on itself and even kill the host and this seemed to me to be a major mechanism by which that was controlled.

Was there a point at which you realised how important the T reg story was?

Prior to my PhD there had been a whole set of literature around suppressor T cells, which were quite poorly defined and not at all what we and subsequently others described as regulatory T cells, but in the early days the scientific community was actually very resistant to that work. After my PhD I did a post doc in Bob Coffman’s laboratory at the DNAX Research Institute in California. They had produced work identifying T cell subsets in mice according to the cytokines they produced. I felt cytokines were key to the function of these different sorts of T cells. There were many more analytic tools over there and I felt that this was a place I could combine the study of both cytokines and T cells. We confirmed that the results that we had discovered in rats also applied to mice. However, the Eureka moment was the publication of a paper describing that the deletion of TGF-β gave you this devastating inflammatory response; I had accumulated evidence that the regulatory cells I was working on were functioning via TGF-β. It was very exciting when these two things came together. We realised that there were going to be molecular mechanisms that we could get at to understand how these cells work and, ultimately, that we might be able to harness them in treating chronic inflammatory diseases.

More recently you have presented a paper describing the role of oncostatin M (OSM) in intestinal inflammation and the prediction of response to anti-TNF-α therapy, which created a lot of interest [1].

Yes, I think it’s probably the aspect of our work that has been most recognised in a clinical context, although we have produced other work that has been clinically impactful. For example, our work on IL-23 defined its role in the context of chronic intestinal inflammation and that is now looking very promising in the clinic. However, the IL-23 work was all in models, and such work of course then needs to be verified in humans. By contrast, OSM was our first study started in humans that then led back into model systems. This iteration is the basis of my lab today.

How did the OSM work come about?

It actually came from a very talented post-doctoral fellow in the lab, Nathan West, who had worked on OSM in cancer and was quite interested in thinking about it in IBD. So he, Ahmed Hegazy and Ben Owens started to look at transcriptomic analysis and started to build some evidence that OSM and the OSM receptor pathway were involved in intestinal inflammation.

Does this discovery of the role of OSM give us any new insights into IBD pathogenesis? In that paper you talked about whether OSM could be an amplifier of inflammatory processes, which would imply that it could be relevant across different forms of IBD.

My own thinking is that OSM represents a distinct pathway, a distinct pathophysiology that represents the interaction between particular cell types. Alternatively, it could be related to the progression of the disease. This still has to be established, but I think it is probably more a distinct mechanism that is related to a physiological pathway where there is a strong mesenchymal cell component. I think what has been captivating about OSM is that its receptor is expressed primarily on mesenchymal cells, fibroblasts and endothelial cells in the gut, and that this is a response of leucocytes talking to fibroblasts in a way that in physiology is helpful for healing, but in pathophysiology becomes deranged or not regulated appropriately. Clearly OSM and OSM receptor are implicated in fibrosis and that is why it has been tested in systemic sclerosis, for example in an ongoing trial. But previously there was no evidence that it was implicated in IBD: this came from Nathan’s work..

What is the future for IBD basic science research?

What we don’t understand is why some patients get IBD driven by one process, and others get IBD driven by another process. Clearly, there’s TNF-dependent IBD; there’s TNF independent IBD; and we are also starting to understand that IL23 is a player, as well as deficiency of autophagy; so IBD is the endpoint of a range of different processes. What we think is happening in IBD is a maladaptation of the host genetic landscape and environmental drivers, and that results in early setting of how the immune system develops, which in turn may dictate the key processes that drive the disease in that individual. What we are trying to work towards with our basic discovery research is to move away from clinical descriptions to a new taxonomy of disease that is process driven. We may even think of going across immune-mediated inflammatory diseases. So, even in diseases such as psoriasis, ankylosing spondylitis and rheumatoid arthritis, we perhaps need to be thinking more about the molecular drivers, rather than discrete clinical features. The processes that are probably the most important are those that are aberrant fundamentally at the beginning of disease pathogenesis, not the end stage. Looking at things this way may allow us to target therapies to those patients most likely to benefit. We’re trying to understand the key pillars that drive intestinal homeostasis: barrier function, phagocytosis, a functional regulatory T cell axis and so on. So, in the future I think we will categorise the disease according to the processes that have gone wrong.

Are you currently collaborating with groups looking at these inflammatory pathways in other organs?

Oh yes, that is our whole raison d’être here, I moved my gut biology and immunobiology lab here (into the Kennedy Institute of Rheumatology) to take a holistic view of immune-mediated inflammatory diseases, because many of the same processes that are involved in IBD are also involved in rheumatological diseases and skin diseases, and so on. We actually have launched an initiative, the Arthritis Therapy Acceleration Programme (ATAP), directed by my colleague Chris Buckley, who is a rheumatologist. One aim of ATAP is to look at setting up interventional “basket trial” studies in humans with a range of diseases including IBD, rheumatoid arthritis, ankylosing spondylitis and Sjögren’s disease. We will look at all these patients together, and test interventions across groups of patients. This will allow us to look at how those pathways are controlled in different diseases and understand the cellular and molecular pathophysiology, with a view to moving towards a more process-driven taxonomy of diseases. So, a large part of what we do at the Kennedy Institute is discovery research. Similarly, in my own research career, I didn’t really set out to have an impact specifically on IBD; I was setting out to understand regulation of the immune response, and of course, when it is not controlled it results in IBD, as well as other pathologies. So, our mission is to discover key processes and then how we can use that information to think about diagnostic and therapeutic tools. Another big collaborative project is microbiome analysis and we are developing capability in that area. We have a Strategic Award from Versus Arthritis and the Kennedy Trust for Rheumatology Research to fund the Inflammatory Arthritis Microbiome Consortium that brings together rheumatologists, microbiologists, computational biologists and immunologists. Our aim is to track changes in the microbiome over time in inflammatory arthritis, and understand its functional role in prediction or the development of disease.

What is your advice to those interested in pursuing a clinical academic or a science career in IBD?

IBD is so exciting. I tell everyone that it’s a great time to be an immunologist, because we now realise that immunology underlies so many different diseases that we hadn’t completely understood before. Furthermore, for many diseases the immune interaction with microbes is key, and that’s just what you’d be studying as a gastroenterologist. IBD is, I think, the poster child for understanding host genetic–environment interactions. Therapeutic targeting of cytokines has been transformative, giving us a lot of new therapies. We can access tissue; the technologies are revolutionising how we think about things, single cell sequencing and so on, and really making it possible to do discovery research in humans in a way that wasn’t possible before. So when you link that into all the other tools, it is a hot field. At the moment we are also seeing many scientists coming into IBD from different disciplines. And of course, there are so many different cell types in the gut – epithelial cells, immune cells, stromal cells, neuronal cells interacting with microbes and dietary components – it’s just fascinating. There are so many things you can discover by taking a deep dive into the gut.

Charlotte Hedin, Y-ECCO Member

Please contact the ECCO Office for any interview suggestions and interact with Y-ECCO on twitter @Y_ECCO_IBD.