Pathway to Independence – an interview with Marcella Birtele

Let's start at the beginning. When did you first become interested in science?

My interest in science started early on in my childhood. My family would go hiking and spend time in nature on the weekends, so I've always enjoyed being outside. That interest was then coupled with science classes because science was one of my favourite subjects in school. When I was introduced to human physiology, I became fascinated by that subject, particularly the nervous system. In elementary school, we were asked by the teacher to write about something in biology that was interesting to us, and I wrote about the nervous system. My mum still has that essay!

I understand that you completed your PhD at Lund University, Sweden. What were you working on at that time?

Yes, I joined Malin Parmar's lab at Lund University. Her lab focuses on developing cell replacement therapies for Parkinson's disease. After pursuing my Master's in neuroscience at the University of Trieste, Italy, I wanted to continue with a PhD focusing on a translational aspect of neuroscience. Dr Parmar's laboratory, being at the forefront of cell therapies for Parkinson's disease, presented an exceptional opportunity that aligned perfectly with my research interests. I was fortunate to be trained as an electrophysiologist under her guidance and Dr Daniella Rylander Ottosson's mentorship, acquiring invaluable skills in probing neuronal function through whole-cell patch-clamp recordings. In my PhD thesis, I worked on dissecting the functional and transcriptional characteristics of dopaminergic neurons, which are important for Parkinson's disease. I explored how different reprogramming methods that transform stem cells into dopaminergic neurons can generate functional cells that can be used for transplantation purposes.

How was the experience of moving to Sweden?

Moving to and living in another country is challenging. I've always loved to travel, but I also enjoy being in a new environment for a longer time. So, I enjoyed living in Sweden and learning a lot from their culture. It was difficult because I was far from my family, but that also helped me because I learned how to become more independent whenever there was a problem or a challenge.

You subsequently moved to the University of Southern California (USC), where you are now a postdoc. What are you working on now?

In the last year of my PhD, I started to work not only with stem cell-derived neurons in monolayer cultures but also on organoid models. That was when I began to appreciate how we can use organoids to understand different aspects of biology or pathology. That's why I joined Dr Giorgia Quadrato's lab here at USC, where her group is leveraging different organoid models to understand neural development. So, I changed the topic slightly from neurodegeneration to neural development, but maintained the idea of using these stem cell-derived models to understand nervous system development and function mechanisms. I specifically focused on SYNGAP1, which is a top autism spectrum disorder (ASD)-associated gene. It was also previously shown to be important for synapse maturation, but its role in the early stages of human development was unknown. For my postdoctoral work, I generated cortical organoids from patient-derived stem cells to understand the biological mechanism underpinning SYNGAP1-related disorders. In our work we found that SYNGAP1 has a role not only in neurons but also in human radial glia cells. Radial glia cells are important for generating the cortex and different neuronal populations. We found that SYNGAP1 played a role in the cytoskeletal remodelling of human radial glia cells. In patient-derived cortical organoids, disruption of the SYNGAP1 gene affected not only the synaptic compartment but also, at the early stages, the cytoskeletal remodelling of these radial glia cells, which impacted the cytoarchitecture of the cortex; in the organoids, this effect was evident from the destruction of the pseudo layering that is usually a characteristic feature of cortical organoids. Later in development, we also saw that the patient-derived organoids had impaired overall neuronal activity. I am now building on this work by including additional patients. SYNGAP1 patients have heterogeneous clinical phenotypes, so we want to stratify and use organoids to understand how the molecular phenotype is linked with the clinical phenotype.

Do you have plans to follow up this work by investigating potential therapeutic approaches?

In the long term, I am very much interested in the translational aspect of research. I like the idea of leveraging human iPSC-derived organoid models for making biological discoveries and then translating that work into a therapeutic approach. That's something I definitely want to pursue in my research.

Did the pandemic impact your move to the US?

Yes, it had a significant effect. I remember being allowed to enter the US only because I was doing research. On my flight from Sweden to the US, I was one of the few people on the plane allowed to enter the country. It was a challenging moment. Starting in a new country and a new lab is already a significant change, so starting in an environment where I didn't meet my colleagues for months and could only enter the lab for a couple of hours a day definitely slowed down my work. Once I entered the US, due to my visa status, I could also not leave the country for almost a year because I would not have been allowed to re-enter. So, I was far from my family and knew I could not exit the US.

How did you hear about Development's Pathway to Independence Programme, and what do you hope to get out of the programme?

I heard about this programme from my current mentor, Dr Quadrato. She knew about the programme and suggested I apply because she knew this could benefit my training. I look forward to hearing advice on managing grants, writing grants and coordinating a lab. Those skills are generally not covered in academic training, so having some courses and feedback regarding those matters is, I think, essential before starting a lab. I am also looking forward to the mentoring aspect of the programme. I think it's very useful to have feedback from someone who is not directly related to your research and who can give you more career advice. And finally, of course, I hope that meeting the other PI fellows will allow me to start creating a solid network of future PIs.

Where are you in the process of securing an independent position, and what has your experience been so far?

I'm planning on starting to apply this fall. Calls are starting to come out right now, so I'm in the process of putting together my application package. It can be overwhelming because it's a lot of different documents, and you want to put your best work forward – consolidating all your experience in a short paragraph can be tricky! But at the same time, thinking about my future research is exciting. Planning new experiments and projects is always fun! It can be challenging and stressful, but it's also a moment where you look to the future, so I'm enjoying it.

What excites you most about becoming an independent researcher?

I am excited to continue doing science. Being able to ask biological questions, including those related to patients, is one of my passions, so the opportunity to keep doing research is valuable for me. The mentoring aspect also excites me. During my PhD and postdoc, I've had the chance to mentor students at different levels, and I've enjoyed seeing them becoming passionate about research. I also love the process of asking a biological question together and then hearing different perspectives on what we can do to find results or solutions to that question. So, I'm looking forward to having my team of scientists just do science together.

You've touched on this already, but what do you think will be the most challenging aspect of being a PI, and how will you prepare for that?

One of the most challenging aspects of being a PI is that the academic career path prepares you for doing science, but it fails to give all the necessary tools for all the other aspects of grant and people management. So, being part of this programme will help me pick up some of the elements that have been lacking in my academic path.

What research questions would you like to address with your own group?

For my postdoc, I focused on SYNGAP1 and leveraging organoid models. I want to expand beyond SYNGAP1 because there are many other top ASD-associated genes that I want to investigate. I am also interested in the finding that SYNGAP1 has roles in different cell types and at various developmental stages. For example, besides epilepsy, individuals with a disruption in SYNGAP1 have major gastrointestinal problems. One of my ideas, linked with my results, is to look at other cell types, moving beyond the central nervous system to explore possible functions of ASD-associated genes in the enteric nervous system, for example. Using organoids, I think you can dissect the mechanisms underpinning these different roles, and so that's what I would like to focus on in the short term. The peripheral nervous system is also known to be involved in neurodegenerative disorders, so, in the long term, I would like to circle back to my PhD work by not only looking at the role and function of these neurons in development but also in neurodegenerative disorders like Parkinson's.

In your opinion, what are some of the most exciting advances in your field?

In the dynamic field of stem cell research, one of the most exciting and promising discoveries is the potential to harness these remarkable cells for therapeutic approaches. The ability to use stem cells as a powerful tool to develop novel treatments and interventions has opened up a world of possibilities, offering hope for countless individuals affected by debilitating diseases and conditions.

However, the significance of stem cell research extends far beyond its therapeutic applications. These versatile cells have also emerged as invaluable resources for unravelling the intricate mechanisms underlying various pathological processes. By leveraging the unique properties of stem cells, researchers have gained unprecedented insights into the intricacies of disease development, progression and potential interventions.

And on the other hand, what are some of the unknowns that you think the field will address in the future?

Stem cells have been revealed to be very useful to understand both biological and pathobiological mechanisms. At the same time, many questions remain, such as how patients' genetic backgrounds can affect a clinical phenotype. The field is starting to understand how, for example, sex or ethnic background can affect the pathobiological mechanism. Addressing those questions is important because they will positively impact therapeutic advancements.

How important do you think mentorship is in navigating an academic career?

I think it is essential. Having mentors you can rely upon is crucial in an academic career. In my experience, I had two great mentors: Dr Parmar and Dr Quadrato. They are two strong female scientists who have guided me through the science part of my career and helped me face personal challenges. In academia, we collaborate and talk with other scientists daily, so I think you can find guidance and inspiration from every person you interact with. Still, dedicated mentors are essential to shaping a scientist's path.

Finally, what do you enjoy doing outside the lab?

Two simple things. Being Italian, the first one is food. It's in my blood to enjoy pasta or a good tiramisu. The other one is my love for the outdoors and hiking, which goes back to childhood memories. These simple things remind me to slow down, savour the little things, and really enjoy what matters most.

Marcella Birtele was interviewed by Laura Hankins, Reviews Editor of Development. This piece has been edited and condensed with approval from the interviewee.