Stephanie Zandee, PhD, recently joined 缅北强奸, where she will be an Assistant Professor in the Integrated Program in Neuroscience, and a researcher and the leader of the Zandee Lab. Joining the Montreal Neurological Institute, Prof. Zandee is the first new Principal Investigator to embark on the Single-Cell Genomic Brain Initiative, studying multiple sclerosis (MS) at the single-cell level. We had the chance to speak with her about her career thus far, and her ambitions in her new role.
Tell us about your research and your career so far.
I started my career at Radboud University (Nijmegen, the Netherlands), where I studied molecular life sciences. I really enjoyed the combination of chemistry and the relationship to disease biology, so I completed a master鈥檚 degree in Molecular Mechanisms of Disease. This is an international honours program, with a cohort of 24 people coming from all over the world each year. It was great to work with people from different backgrounds and cultures. As part of the program, I completed an internship at the University of Edinburgh. I was particularly interested in the intersection of neuroscience and immunology, as such MS was a highly relevant field of study. I studied MS lesion pathology and created a method to study up to 7 different markers simultaneously to understand lesions better. I became interested in anti-inflammatory regulatory T cells, and why they don鈥檛 behave normally in MS patients. I completed my doctorate deepening my understanding of this phenomenon. I also worked in mouse models of MS, using machine learning on immunofluroescent images of lesions.
For my postdoctoral studies, I joined the laboratory of at the at Universit茅 de Montr茅al (UdeM), to further explore the regulatory T cells migration over the blood鈥攂rain barrier. During my postdoctoral fellowship, I was leading the MS Brain Bank and rapid autopsy program, where I will continue to help out now. I also collaborated with , at Universitat Aut貌noma de Barcelona, looking at cytokine IL-37 in MS mouse models. Though we don鈥檛 know much about this anti-inflammatory cytokine, we know it plays a role in autoimmune diseases and cancer. In the case of autoimmune diseases, people with higher levels of cytokine IL-37 tend to have better disease outcomes. In mouse models of MS, we found that higher expression of it was associated with less influx of immune cells into the spinal cord and brain, and less demyelination. In one of my postdoctoral projects, I looked at the effect of IL-37 on the blood-brain barrier. We also found cells in the Central Nervous System (CNS) that can make cytokine IL-37, potentially hinting at a self-regulatory mechanism to treat inflammation in the brain. This is what I am to investigate further with my lab.
How will the Zandee Lab integrate these findings and advance MS research?
The lab鈥檚 overarching goal will be to look at MS pathology, and the underlying factors and molecular underpinnings which govern the timing and the location of lesions. Following up on my findings with Prof. L贸pez-Vales, I want to study cytokine IL-37 during homeostasis and CNS inflammation to better understand its role in the brain and explore its potential as a treatment by triggering its expression. We will use a combination of techniques and modalities, such as single-cell RNA sequencing, neuroimaging and flow cytometry. In collaboration with researchers at , we will be using multimodal analysis and machine learning to combine the findings from these different methods to try and discover underlying disease patterns.
Why do you want to use single-cell technology for your research?
Other techniques, such as bulk RNA sequencing, have been helpful and provide a lot of information. However, the patterns we extract from them include a combination of cell types in different states. We don鈥檛 know if the information comes from cells in homeostasis or in disease state. The benefit of single-cell sequencing is that we can tease apart these different cell clusters. Adding spatial sequencing, we could then see where these cells are in the tissue and in the actual lesion. Technology has evolved and we are now able to get spatial sequencing at a single-cell resolution. This combination of single-cell and spatial sequencing is ideal to understand what is happening, and where.
Was there a specific event that inspired you to study multiple sclerosis?
There are two that come to mind. During my internship and my PhD, I used confocal microscopy to develop a staining method looking at as many biomarkers in tissue as possible. I managed to design a method that can measure seven different markers simultaneously, which was a huge accomplishment. I was also learning how to use machine learning methods to take into account the vast amount of information coming out of this method. Looking at machine learning analysis, I wondered how we could do this for hundreds of thousands of molecules to really understand what these cells are doing, how they communicate with each other, and what causes lesion development. Realizing how machine learning could help science move forward was a big moment and I wanted to be a part of that.
Another big moment was when I accompanied a neuropathologist to see the brain of a human being, all while respecting the patient鈥檚 dignity and sacrifice. These individuals donate their brain to science to help others with the same disease. Holding that patient鈥檚 brain and seeing their lesions, you can鈥檛 get much closer to the disease. I know I can鈥檛 help that person anymore, but I hope I can contribute to their wish of granting a better life for those who are still alive.
Tell us about your collaborations to enhance the impact of your research.
I will continue collaborating with Dr. Prat at UdeM, working with brain tissues from the Brain Bank. At The Neuro, I will be collaborating closely with Adil Harroud, MD, Jack Antel, MD, Jo Anne Stratton, PhD, and also with . Dr. Harroud is a specialist in MS genetics, Dr. Antel is an expert in oligodendrocytes (the cells that produce the protective myelin sheath surrounding neurons), Prof. Stratton is more focused on ependymal cells, while Dr. Moore is studying contribution of the choroid plexus to lesion formation. The Zandee Lab will focus on differences between periventricular and deep white matter lesions. The five of us will bring our combined research in these different brain areas together, and it鈥檚 a great opportunity for us to get a more complete picture of what鈥檚 happening. At the Ludmer Centre, I鈥檓 very interested in working with Corina Nagy, PhD, and plan on using tissue from the Douglas Bell Canada Brain Bank. I鈥檓 very interested in doing nuclear sequencing, which Prof. Nagy and Prof. Stratton are both experts in. I look forward to all these collaborations.
How will your research contribute to the development of new treatments or diagnostic tools?
Studying the disease at the single-cell level will allow us to look at the disease states of the different cell types, and to better understand the disease progression and its different phases. It could potentially help us identify the pathways that are up- or down-regulated and give us a better candidate for what mechanism to target for treatment options. Many of the existing treatment options target the immune system, but none target the brain itself. If we can find the specific mechanism in the CNS or have a better understanding of what鈥檚 happening in the lesions, we can really improve the lives of the patients. At The Neuro, scientists are developing Positron Emission Tomography (PET) tracers for inflammation in the brain which can be used to follow patients over time and see the response to different treatment options in the future. If we can identify more non-invasive imaging-based targets through single-cell sequencing, that would be amazing.
Why did you decide to stay in Montreal and at 缅北强奸?
There are a lot of collaborations happening across Canada. People are reaching out to help each other, and I really like this environment. At 缅北强奸, there are a lot of collaborations between the people in the MS field, like the ones I mentioned earlier. Montreal is a beacon of hope in neuroscience research, and there is a particularly good MS hub here. From clinical to neuroimaging, to single-cell and nuclear sequencing, there is a community of researchers looking at different aspects of MS. It鈥檚 the whole package.
What are your vision and your mission in building your own lab? What values do you want to pass on to the next cohort of scientists?
I want to create a space where we are continually learning from each other. It鈥檚 great to see the student trajectory from when they first enter the lab, start to gain confidence, and come up with their own interpretation and ideas. Each new cohort brings new ideas and perspectives, and it鈥檚 a privilege to witness this journey as they become their own scientists. I鈥檝e trained a lot of students in the past, and I look forward to welcoming my first master鈥檚 student, Sara Chafik, this fall. In the Zandee Lab, I want to cultivate a passion for multidisciplinary approaches in science. More and more, we see the involvement of multiple systems in different disease mechanisms. We need to start looking over the bounds and borders of our own field for different experts to come together, learn from each other and expand our knowledge to more than one system. I would like my trainees to think outside the box and learn from other disciplines.
Anything else you鈥檇 like to mention?
I鈥檓 thankful to everybody who鈥檚 helped me along the way. I鈥檝e had great teachers and mentors and amazing opportunities. Sometimes these were my supervisors, but there were also people from other labs or just a bit ahead of me in their career. I鈥檓 part of the , a society where different researchers support each other. I first joined as a mentee and am now in a place to offer mentorship. It鈥檚 nice to be able to receive support, but to also be able to pay it forward. Of course, your lab supervisors are the obvious mentors and will help you find your path; all these other mentors are just as important for you to progress in your career. You don鈥檛 become an assistant professor overnight -听it takes a village.
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