Generation of Human Subtype-Specific Interneurons for Therapeutic Replacement and Disease Modelling

What have you been working on during your time as a Ph.D. student?

“My PhD studies have focused on generating human subtype-specific interneurons for therapeutic replacement and disease modeling. 

Interneurons are important for proper brain function, and they are often lost or dysfunctional in many neurological disorders, such as epilepsy and schizophrenia. So, it is very important to be able to generate them in the lab, both as a potential cell therapy strategy to replace lost neurons, and as models to study disease mechanisms and develop new therapeutic approaches.

We worked with two different techniques. One is direct reprogramming, where we use human glial cells (supportive cells) and convert them directly into Parvalbumin (PV) interneurons. This can serve as an alternative to more traditional stem cell-based approaches, enabling conversion of resident glial cells directly in the brain.

The second is a stem cell differentiation approach, where we established a model to generate another type of interneurons of somatostatin (SST) type in a 3D co-culture system. We then used this system on patient-derived induced pluripotent stem cells (iPSCs) to model schizophrenia and investigate potential disease mechanisms.

One thing I would really like to highlight is that in both approaches we showed that the interneurons we generated are very similar to the endogenous ones. We compared them to publicly available datasets of human brain development, and through bioinformatics analysis we confirmed their similarity.

This is very important, because if you want to replace cells or model disease, you need something that is as close as possible to what exists in the human brain.”

Why is this type of research important?

“The human brain is extremely complex, and many aspects of neurological disorders are difficult to model in animals. At the same time, access to human brain tissue is very limited.

Advances in our knowledge about human brain development have been made through many single cell and single nuclei sequencing studies, and as well as stem cells. Being able to generate the relevant human cell types in the lab allows us to study their development and understand the disease mechanisms that contribute to the disease pathogenesis in a way that was not previously possible.”

Can you tell us about the cover of your thesis?

“In the center, there is a brain, and on each side, there are two different populations representing the two types of interneurons I generated, SST and PV. They are shown in different shapes and colours.

The idea is that these two populations are coming through portals to try to ‘save’ the brain.

I came up with the concept myself and then worked together with a graphic designer, who is actually my partner’s father, so it is a 100% human-created cover.”

How did you end up doing a PhD at Lund Stem Cell Center?

“My interest in science goes back to high school in Greece. Biology, chemistry, and physics were always my favourite subjects. I was especially fascinated by cells and genetics, particularly the role of DNA as the fundamental molecule of life.

For my bachelor’s, I studied molecular biology and genetics in Greece, in a town near the border with Turkey, and during that time I became very interested in stem cells and their regenerative potential. The idea that you can generate almost any cell type and use that for therapy or disease modeling was very exciting to me.

When I started looking for Master’s programmes, I found the Lund Stem Cell Center and thought, ‘this is the place for me.’ I moved to Lund in 2019 to study biomedicine, here at Lund University.

During my Master’s, I was looking for an internship at the Lund Stem Cell Center. My CV was shared among research groups, and Daniella contacted me because they needed someone for a project.

I joined her group in early 2020, did my Master’s thesis there, and then continued for my PhD. I really liked the group, the project, and the overall environment, so it felt like the right place to stay.”

What has been the most enjoyable during your PhD?

“One of the most enjoyable aspects has been the sense of community.

Both the Lund Stem Cell Center and MultiPark, the two strategic research areas that our research group belongs to, have organized many retreats and seminars and other events. These have all been great opportunities for the PhD students to come together, exchange ideas, support each other and feel part of a larger scientific community.

The Professional Development Program (PDP) through the Research School in Stem Cell Biology has also been a very important part of my studies. It provided us with many important skills for our future careers. It has also been a great support system among the PhD students; it was a very safe space for us to really express our feelings and our thoughts with respect and judgement.

But I think the most enjoyable aspect is the feeling of generating new knowledge.

You sit in front of your computer, analyse data, and suddenly you see something interesting. You realise, ‘this is something new, we can publish this.’ Then you go to your PI, discuss it, and start shaping it into a story.

It’s the feeling of contributing your own small stone to the pool of scientific knowledge. That has been the most rewarding part.”

What has been the most challenging part?

“The PhD journey can sometimes be a very lonely one. You are responsible for one project that maybe no one else can fully help you with, so you need to be ready to figure things out independently. At the same time, you are juggling many different tasks: running experiments, analyzing data, writing manuscripts, replying to revisions, and mentoring students. It is important to find balance between all these tasks. 

Maintaining a good work-life balance or as we learned in the PDP “work-life integration,” is challenging. Work is part of our life, not something separate; it is important you manage it in a sustainable way.”

What are your plans following the defense? 

I will stay in the lab until the end of June to wrap up some projects. After that, I would like to find something in the Öresund or Gothenburg area. I am mainly looking for scientist positions in R&D but am also exploring other opportunities within life sciences, such as a management consultancy. I’m interested in using my transferable and soft skills to help solve challenges in biotech and pharma. That said, I’m also keeping the option of pursuing a postdoctoral position open.

Through the PDP program, I was matched with a mentor who is in the life science sector. They have been helpful in connecting me with people in the life sciences industry and gain a better understanding about different positions and career paths.” 

Do you have any advice for future PhD students?

"One important thing is to build a support system within your lab, your floor, or through communities like the Lund Stem Cell Center or PDP. At the same time, try to have a life outside of the lab, outside of academia. It is important you have your activities, your hobbies, and your non-scientist friends. It gives you perspective and helps to you disconnect when needed, so that you are not speaking science all the time. 

Another piece of advice is to choose the lab that you are going to do your PhD with very wisely. If possible, do your master’s thesis there, or a small internship, or something similar. This is helpful so that you get to know each other, know your supervisor, see the lab dynamics, and if you like the project and the town before proceeding. 

A PhD is a big commitment, it is at least four years of your life, so it is important that you choose a place where you feel comfortable and supported.”