First person – Joe Tyler Free

Joe Tyler

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

Every cell in your body needs to be able to respond to the world beyond it, but not all cells need to respond the same way to every stimulus. White blood cells, for example, are very sensitive – they need to move around the body and quickly recognize and respond to signs of disease. However, cells within a tissue must maintain an ordered, organized environment and so can't start moving independently in response to every external signal. Cancer progression can be imagined as a change in how a group of cells responds to external stimuli. Cells might start to divide or move around when they shouldn't. Here, we identified a new role for a group of proteins, the class 1 PAKs, in controlling the sensitivity of the cell to external stimuli. This could be important, as the activity of these proteins has already been shown to be disrupted during cancer progression.

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

Something that I found challenging during this project, but also very rewarding, was getting to grips with cortical excitability and actin waves. This area of cell biology was new to me, and both the amazing body of literature and the results we were getting forced me to change the way that I was thinking about the cell. This developing obsession with PIP₃ and actin waves also directly shaped the next step of my career, motivating me to contact my current boss, Jason King.

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

The eureka moment for me came the first time I observed the response of cells to class I PAK kinase inhibition live under the microscope. Using low resolution brightfield microscopy, I saw that very soon after adding the drug, nearly every cell produced a large protrusion that dramatically changed its shape and the way it migrated. ‘Seeing is believing’ and that is one of the wonderful things about live cell microscopy! This moment started an obsession for me, and I was really happy that I was able to include this experiment in the paper as Movie 1.

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

I saw a great presentation at the 90th Harden: European Cytoskeletal Forum that clearly expressed the importance of JCS, particularly emphasizing the importance of society journals. Additionally, I have always enjoyed reading papers in JCS and think how well they are presented, both online and in PDF format, which I felt was important. My experience submitting to JCS has been very good and I would definitely consider submitting again in the future.

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

It was great working with my fellow first author Anthony Davidson, who is now at EtCembly. He really helped keep me on track and focused, and it was great to work with someone whose skills complemented my own so well. I also really appreciated the discussions I had with Helen Mathews, a Principal Investigator here in Sheffield. She gave me great advice when I was struggling to write the paper. She (very nicely and accurately) pointed out that I was struggling to write the paper because it was more fun to be in the lab doing experiments. This comment made me reflect on why this was the case: why did I love talking about this work but not enjoy writing about it? This led me to change the way how I was writing the paper – I began to focus on what I loved about the work. I think the final paper is much stronger because of that shift.

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?

A lot of it was blind luck, I think. At 17, I was very close to applying to study economics at university. The week before I was due to submit my application, my chemistry teacher showed us a video about molecular machines, which included a cartoon of a kinesin ‘walking’ along a microtubule. I thought it was absolutely amazing. I threw away all my economics applications and applied to study biological chemistry instead. Another bit of blind luck was that the course I chose was an integrated master's. Tuition fees were still relatively low at the time, and I didn't give it any more thought beyond: ‘Four years must be better than three’. That fourth year, however, contained a good chunk of time in a research lab. I would never have dreamed of doing a PhD without that experience, I don't think I even understood it was an option before then.

Who are your role models in science? Why?

The work of the poet Kathleen Raine has been helpful to me both in my personal life and throughout this project. Though maybe not ‘in science’, she studied natural science in the 1920s and clearly had a very well-developed understanding of the cutting-edge biology of her time. I find the way she treats time in her poetry provides a constructive framework for thinking about the repetitive cycles of cortical excitability we have described here. Additionally, I love her series ‘three poems on illusion’, the second of which (Exile) contains the important reminder to somebody searching for the secrets of life that ‘Cells, spindles, chromosomes, Still merely are’ and they ‘Declare I am and remain nameless’. I think this is an important reminder, particularly for light microscopists. Despite our best intentions, we are often limited by the nature of the technique – we often only see the part of the picture that we are looking for. I think this limitation is well illustrated in work showing the regulation of clathrin-mediated endocytosis or the glycolytic machinery by ‘actin’ waves; the actin part of the wave is very easy to observe, but the full identity and consequence of these structures remains to be explored.

What's next for you?

I am very happy here in Sheffield and in my postdoc position in Jason Kings lab. Beyond that, I really don't know.