First person – Frances Tilley

Frances Tilley

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

The environment of a cell has an impact on how that cell behaves, in the same way that the behaviour of humans and other animals is influenced by the circumstances in which they find themselves. Whereas humans have eyes, ears and a nose to sense their surroundings, cells instead have to rely on protein ‘sensors’ embedded in their outer membrane. These sensors are in a constant state of flux, as cells will internalise the sensor molecules to relay the signal to its nucleus (the ‘brain’ of the cell in this analogy) and then recycle the sensor back to the membrane where it can be reused. Mutations in proteins that regulate this internalisation and recycling of cell membrane sensor molecules underlie a number of human diseases, as it means the cell cannot respond properly to changes in its environment. For example, some cases of autosomal dominant polycystic kidney disease (ADPKD) are caused by loss of a protein called polycystin-2 (PC2) from the surface of a type of kidney cell. In this article, we describe a link between retromer, a protein known to be involved in cell membrane sensor recycling, and PC2, suggesting that retromer could have a role in the development of ADPKD.

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

The challenge in this project was to test our hypotheses in a more physiologically relevant model system. Our lab has traditionally been concerned with the basic cell biological mechanisms of endosomal trafficking, and we have traditionally used HeLa and retinal pigment epithelial-1 (RPE-1) cells for our experiments. The initial identification of polycystin-2 as a putative retromer-interacting partner, and the immediate implication that retromer could also have a role in ADPKD pathology, caused us to seek collaboration with a lab that was specialised in the sort of physiological assays we needed to advance the project. Luckily, we were able to establish a link with the Zhou lab at the Harvard Polycystic Kidney Disease Center, who were able to help us enormously by performing PC1 ciliary trafficking assays as a read-out of PC2 function in kidney tubule cells.

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

My favourite moment of this research project was the first time I looked at cells expressing a GFP-tagged PC2 construct that was lacking its carboxy-terminal domain, co-stained for the retromer component VPS35. I had hypothesised that perhaps I was not seeing colocalisation or co-immunoprecipitation between overexpressed full-length PC2 and retromer because exogenous PC2 was trapped in the ER, but I was still surprised to see how once the ER-retention site of PC2 was removed, PC2 became almost totally colocalised with retromer-marked endosomes.

Have you had any significant mentors who have helped you beyond supervision in the lab?

My supervisor, Prof. Peter Cullen, was a great mentor throughout my PhD. In particular, he helped me see at what point it is worth pursuing hypotheses, at what point it is more productive to move on to something else, and also to be positive about the work I have done. In addition, my current supervisor, Prof. Corinne Antignac, has helped me to develop confidence in my abilities to direct a research project, and to keep in mind what I want as an outcome, particularly as it relates to further understanding a cellular process in the context of patient interests.

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?

I have been motivated to pursue a career in science since I took part in the summer student programme at the Cancer Research UK London Research Institute in 2011. Although I have always been interested in science, I was totally enamoured by the fact that the people I met at the LRI had almost total control over their work, and had the privilege to work on something that fascinated them every day, which was also in the interest of improving the lives of people with cancer. I met people from all over the world at the LRI, and also wanted to work in a field where I would both have the chance to travel, and to work with people from cultures different to my own. One of my most interesting experiences in my scientific career so far was a short internship I did at the Institute of Food Research (now the Quadram Institute) in Norwich. I was in the lab performing microarray analysis, but the lab I worked in was also carrying out an intervention study, looking at the effects of ‘super broccoli’ on cardiovascular health. I spent a few afternoons in the fields by the institute, helping to harvest the super broccoli.

Who are your role models in science? Why?

I have to say that my scientific role model is Dr Britta Weigelt, who I met during my internship at the LRI. I was inspired by the passion and enthusiasm with which she approached her work on gynaecological cancers, and by her subsequent career progression towards a group leader position at the Memorial Sloan–Kettering Cancer Center.

What's next for you?

I am currently just over a year into my first postdoc at Imagine Institute in Paris, where I am working to uncover the mechanism of disease in a subset of Galloway–Mowat syndrome (GAMOS) patients. GAMOS is an extremely rare nephrocerebellar syndrome affecting mostly children, and I am hoping to stay at Imagine for the foreseeable future, working up the results I have into a more complete story, and improving my French.

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

I recently provided the voice for a tent in a promotional video for a chain of French sports shops.