When I started my PhD in late 2019 at the University Medical Center Groningen (UMCG), I was given a challenging task: develop a human model of phospholamban (PLN) cardiomyopathy. At that time, our department had extensive expertise studying the disease in mouse models, but many questions remained unanswered regarding how this disease develops in human cells. The goal was ambitious: create a human in vitro disease model, unravel disease mechanisms, and ultimately identify treatment strategies that could improve the lives of patients carrying PLN mutations.
What has always driven me in science is not only the biology, but the patients. My heart lies with translational research, research that continuously asks: how can this eventually help someone? Genetic diseases, to me, feel fundamentally unfair. Patients can live with healthy lifestyles and still face severe illness simply because of the genes they inherited. That sense of unfairness is one of my strongest motivations for studying genetic heart disease.
PLN cardiomyopathy has a particularly strong impact in our region of the Netherlands. In our academic center, approximately 10 to 15% of patients with arrhythmogenic or dilated cardiomyopathy carry PLN mutations, making it one of the most prevalent inherited cardiomyopathies we encounter. Although conventional heart failure therapies can provide support, they often fail to halt disease progression. Over time, many patients continue to deteriorate and may eventually require advanced interventions such as left ventricular assist devices or heart transplantation. Ultimately, our goal is simple: preserve quality of life and prevent the heart from progressively failing.
Only a few months after beginning my PhD, the COVID-19 pandemic disrupted laboratory research worldwide. Like many early-career researchers, I experienced delays and unexpected obstacles that significantly changed the trajectory of the project. Beyond the pandemic, the scope of the project gradually expanded. Alongside developing a human disease model, the work evolved to include obtaining ethical approval, initiating the DECIPHER-PLN cohort, founding the UMCG heart tissue biobank and generating patient-derived cell models and datasets.
Research itself also brought unexpected practical challenges. Some of our experiments depended on access to human cardiac tissue. Initially, we aimed to collect samples from ten donor hearts, but tissue availability often dictated the pace of the project. After several years of tissue collection, we made the decision to move forward with the material available and shift our focus toward generating and integrating experimental data. Along the way, technologies evolved as well. Early calcium imaging experiments relied on fluorescent indicators and conventional fluorescence microscopy, but during my PhD our department acquired a CytoCypher platform, which dramatically improved both throughput and experimental possibilities. As with many long-term projects, technological advances continually reshaped the way experiments were performed and opened new opportunities that had previously not been possible.
Another challenge involved phosphoproteomics, a rapidly developing technique that became central to this work. We became interested in phosphoproteomics because many kinases and phosphatases are highly sensitive to intracellular calcium signaling. Since PLN itself is a key regulator of calcium handling in cardiomyocytes, we wanted to understand how a pathogenic variant in a calcium-handling protein could reshape the cardiac phosphoproteome and downstream signaling pathways. While the novelty of phosphoproteomics created exciting opportunities, it also came with uncertainty. Data interpretation was often difficult because the biological function of many phosphorylation sites remains unknown, and finding experts able to help interpret these complex datasets was not always straightforward. Like many emerging technologies, phosphoproteomics offered a lot of freedom, but also required learning to navigate unanswered questions.
Research also taught us an important lesson about disease modeling itself: sometimes the phenotype you are searching for is simply not there. Early in the project, we struggled to identify a clear disease phenotype in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) under conventional culture conditions. At first, this was frustrating and raised difficult questions. Were we looking at the wrong readouts? Was the model insufficient? Or were we missing an essential aspect of the biology?
Over time, we realized that the answer might lie in cardiomyocyte maturation. Phospholamban is often considered a maturity-associated gene, with relatively low expression in immature iPSC-CMs and increased expression as cardiomyocytes acquire a more mature phenotype. A key breakthrough came through the work of my talented colleague, Karla Arevalo Gomez, who developed a fatty acid-based maturation medium capable of functionally maturing iPSC-CMs. Only after applying these maturation strategies did the disease phenotype begin to emerge in vitro. Looking back, this became one of the most important lessons of the project: sometimes understanding a disease first requires understanding the biology of the model itself.
As the years progressed, experiments accumulated and the challenge gradually shifted from generating data to making sense of it all. Much of science is not simply producing results, it is figuring out how to tell the story hidden within them.
Seeing this work eventually receive international recognition has been deeply rewarding. The research surrounding this project was nominated multiple times for Young Investigator Awards from the Heart Failure Association and ultimately received the Young Investigator Award in Basic Science at Heart Failure 2026 in Barcelona. It also received the Durrer Prize from the Dutch Society of Cardiology and several grant, presentation and poster awards. Most importantly, however, this work became the main part of my PhD thesis, which I had the privilege to defend on March 25, 2026, in the beautiful Academy Building in Groningen, the Netherlands.
Looking back, what began as a project to model phospholamban cardiomyopathy ultimately became about much more than science alone. Meeting patients, hearing their stories, shaking their hands, and involving them in our studies continually reminded me why this work mattered and gave me the motivation to keep moving forward. Seeing patients endure difficult procedures, surgeries, and uncertainty, yet still recognize the importance of research and willingly contribute to our studies, was a constant source of inspiration. Their stories transformed research from an academic pursuit into something personal.