Louis Prahl is a postdoctoral fellow in Alex Hughes' lab in the Department of Bioengineering and the Center for Soft and Living Matter at the University of Pennsylvania, Philadelphia, USA. He is interested in how epithelial cells organise into complex structures and in developing engineering strategies to control tissue organisation. Louis is one of the 2024 fellows of the Pathway to Independence Programme. We caught up with him to talk about his physics and bioengineering background, his interdisciplinary research interests, and his plans as an independent researcher.
Let's start from the beginning, when did you first become interested in science?
My dad was a professor of geochemistry and oceanography, and occasionally as a family, we would visit his field sites in places like the Columbia River Estuary. I have always been broadly curious about the natural world. Growing up, I had all these books about the animals you'd find on the Oregon coast. When we visited the coast, I would go to the tide pools and see if I could find the things mentioned in books. By the time I entered college, I was sure that I wanted to study astronomy, but the class that really resonated with me was a modern physics class that was taught by a biophysicist. I loved physics because it had built-in rules and structure. It was appealing to be able to understand things through maths, rather than memorisation. Learning about biophysics made me realise there's a way for the two worlds to come together.
How did you come to do a PhD in biomedical engineering with David Odde at the University of Minnesota?
I was attracted to biomedical engineering because it integrates different perspectives and has the potential to benefit human health. I saw it as an interdisciplinary hub. When I finished college, I worked with Dr Bethe Scalettar, a professor of physics at Lewis and Clark College where I went to be an undergraduate. I knew I wanted to eventually go to grad school, but I was not sure in which field. I worked for 2 years at the Oregon Health and Science University as a laboratory technician and clinical research coordinator. During that time, I attended talks by biomedical engineers and heard about research such as the movement of the inner ear hair cells and how that relates to hearing. I realised I could use my physics background in a different context. When I was applying for PhD programmes, Dave Odde's lab particularly appealed to me because he takes a holistic modelling-based and physics-based approach to understand how a cell works and how to therapeutically intervene in processes like cancer cell migration.
What did you work on during your PhD?
When I joined Dave's lab, he was working on two different things: cancer cell migration and how microtubule dynamics respond to chemotherapy drugs. I decided to merge the two. I studied how actin and microtubules interact during migration, and how chemotherapy disrupts that process. There had been decades of papers showing that cells are acutely sensitive to chemotherapy drugs in very small concentrations. Different observations led to different models of how the drugs perturb cell migration. I decided to systematically test the models using a simulator of cell migration and relate that to experiments of cells migrating in various environments and under different treatment conditions. The principles that we established could be easily applied to other cells and biological contexts, which I think is an exciting aspect about the approach we took.
You are now a postdoctoral fellow in Alex Hughes' lab at the University of Pennsylvania (Penn), USA. What made you decide to switch from cancer research to developmental biology?
When I was thinking about where to do my postdoc, it was around the time when many physics-driven embryology papers were being published. I was fascinated by processes like epithelial tissue remodelling and fluid to solid jamming transitions, which happen at larger length scales and different time scales than the cells I had studied in my PhD. I was interested in using modelling and engineering approaches to understand large-scale processes involving multiple interacting populations of cells. Alex is an engineer, so we had some common background, and he had just started his lab at Penn and was recruiting a postdoc. We're interested in the same kind of things and I could see my background fitting in with Alex's lab.
Can you talk about the project(s) you're working on as a postdoc?
I've jumped around a little bit and worked on a few things in the lab. By and large, I'm interested in how the embryonic kidney epithelium branches and how this branching morphogenesis process forms a properly organised and interconnected network of tubules and nephrons that's required for function. The kidney is a fascinating organ. It's also a hot spot for congenital anomalies. Given that there's a significant population of people with chronic kidney disease, I'm also interested in modelling these congenital anomalies to understand how they arise, and how we could use this to inspire potential future treatments, such as gene therapies or lab-grown replacement tissue. During lockdown, we had all been working on computational projects, and Alex came up with a geometric computational model for tubule organisation that we would discuss during our virtual meetings. Coming out of lockdown, we decided to try testing the model in mice. Fast forward to now, we've found some ways to synthetically perturb mouse tissue and recapitulate some of these organisational defects, as well as some new biophysical measurements. We are looking at the spatial organisation of tubules and nephron niches, and trying to identify and understand the physical forces involved in this process. This has led to some interesting kinds of insights into how jamming physics might pertain to tissue-scale organisation. I've switched back to cell-to-tissue scale projects, and am currently working on trying to engineer branching tubule networks using optogenetics, activating some of the signalling pathways that guide the formation of branches with precise spatial and temporal control.
When you start your own group, do you wish to continue incorporating your physics and bioengineering background into your research projects? What research questions will you want to address?
I would like to engineer epithelial cells and developing tissues, and to better understand organisational principles like branching. How do cells create a branched network in the first place? How do we recapitulate that in the dish? Many organs contain tubular networks but the architecture is different depending on the organ. Given there are long transplant lists for many organs, I hope we could eventually use tissue engineering strategies for organs like the lung or the pancreas.
I'm also interested in the idea of engineering boundary formation and controlling processes like epithelial mesenchymal interactions. These developmental processes create stereotyped, repetitive structures with high fidelity, and that's the goal of tissue engineering as well. I think there's an opportunity to dig into my bioengineering background and use systematic modelling approaches to understand how biophysical changes within cells relate to their differentiation state and to morphogenesis processes.
There's an opportunity to dig into my bioengineering background and use systematic modelling approaches to understand how biophysical changes within cells relate to their differentiation state and to morphogenesis processes
How did you hear about Development's Pathway to Independence Programme? Why did you decide to apply and what do you hope to get out of it?
I first heard about it through social media. I am familiar with The Company of Biologists and its journals. The Pathway to Independence (PI) Programme appeals to me because, one, it would be great to have a cohort of new PI friends, all starting around the same time; second, I have an interesting interdisciplinary niche that I'm exploring, so I hope to take advantage of this programme and target my materials for the types of interdisciplinary programmes I'd fit best in. I've been partnered with Jim Wells as my mentor, and he has a lot of experience in stem cells and organoids, which is an area that fits well with my interests.
What are the factors influencing your job search and where are you in the process at the moment?
I submitted a round of applications last year and was interviewed for a few places, so I know that I can be competitive. When I envision my lab, I would like to have a place where engineers, biologists and, potentially, clinicians communicate and solve problems together. The right fit for me means I want to be in a place where I have access to both an engineering and a biology community, and can recruit students from both. A few other personal factors can also influence my job search. I'm from the USA, but I'm open to places across the USA and Canada, and potentially Europe, and I will also be coordinating opportunities with my partner. It ends up being a very multifactorial decision process.
What excites you the most about becoming a PI?
I'm excited to have the freedom to steer a group of intellectually curious people and learn new things together. The other thing that I find really appealing about being an independent researcher is choosing and maintaining collaborations with people from different fields. I enjoy being in an interdisciplinary field.
I hope to get some training from the PI Programme and hopefully, further on down the road, I can pay that forward to other new PIs
What do you think are the challenges of becoming a PI?
The biggest challenge is that, all of a sudden, I will have to do things that I've never done before. The challenge will be to figure out how to do them as quickly and efficiently as possible. A new PI recently told me they had to submit a floor plan for the lab – I haven't even had to think about this for a house! And a house doesn't have tissue culture hookups or compressed air lines that I need to consider. Starting a lab from the beginning will take time. I still remember coming into Alex's brand-new lab and learning that there was a lot happening behind the scenes that most postdocs don't see. Managing all the newness and uncertainty is what I see as the biggest challenge. I hope to get some training from the PI Programme and hopefully, further on down the road, I can pay that forward to other new PIs.
Who have been the key mentors during your career and how do you think they will influence your own mentorship style?
Every mentor I've had has been different. I like to think I've taken little bits and pieces of mentorship styles from different people. I appreciate having mentors who give me guidance, but also give me the freedom to pursue something. Both Dave and Alex have been very supportive and encouraging of me to apply for things and try stuff. During my PhD, I had the opportunity to apply for international research support through the NSF Graduate Research Opportunities Worldwide (GROW) programme. Around the same time, I met Matthieu Piel at a conference and really enjoyed hearing about his work on confined cell migration. Dave and Matthieu had been interested in working together, because Matthieu has these micro channel-based devices that resembles the confined conditions found in brain tissues and we could use these to test cell migration models. GROW funding allowed me to train with Matthieu in Paris for 3 months. I learned new techniques and brought them back to Minnesota and they became part of my PhD work. I also got to build a network overseas, which was great.
It was the same with Alex during my postdoc. He mentioned that the Woods Hole Marine Biological Laboratory (MBL) physiology course was really influential to him as a scientist. He thought I would benefit from one of the Woods Hole courses and encouraged me to apply for the embryology course. I think it was an incredible experience, scientifically and socially, as we were just coming out of the pandemic lockdown and we were able to do science with other people again. Huge kudos to the 2021 course directors, David Sherwood and Carole LaBonne, for pulling that off.
Mentoring people at different levels is going to be very new for me. I have worked with undergraduates and rotation students, so I think I know a bit about my mentorship style at this point. I know that it has to be different for everyone. I have to be cognizant of how different people respond to being mentored.
Finally, what do you like to do outside the lab?
I like to keep active. I'm a runner. I like cycling and, occasionally, rock climbing. I enjoy being outdoors, especially hiking and bird watching. And when I want to be indoors, I like board games and cooking. I also enjoy the great music scene in Philly.
Louis Prahl's contact details: Department of Bioengineering and the Center for Soft and Living Matter, University of Pennsylvania, Philadelphia, PA 19104, USA.
E-mail: [email protected]
Louis Prahl was interviewed by Joyce Yu, Online Editor at Development. This piece has been edited and condensed with approval from the interviewee.