Thesis Defense Sarah Kamel: “Modeling human cardiac genetic diseases in the zebrafish”

Cardiomyopathies are diseases of the heart muscle. The heart undergoes cellular and structural changes that affect the ability of the heart to contract and thereby impair heart function. These changes eventually lead to heart failure. During her PhD research, Sarah Kamel used the zebrafish as a model to study a specific genetic mutation (RK94del) in a cardiac gene called Troponin T (TNNT2), known to be involved in the origin of cardiomyopathies. She found that, similar to human patients, the zebrafish carrying this mutation suffered from changes in the size of the heart chambers, as well as increased calcium sensitivity and impaired ability of the heart to contract. Given the similarity of the zebrafish model compared to humans, it may be a promising model to identify possible therapeutics for the disease. The results of this study were published earlier this year.

Publication in Nature Communications

Additionally, Kamel induced a patient-specific genetic mutation (R14del) in a cardiac gene called Phospholamban (PLN), to study its effects on the progression of a specific type of cardiomyopathy called arrhythmogenic cardiomyopathy (ACM). Together with her colleagues, she discovered that zebrafish with this mutation showed the same symptom of ACM as human patients: healthy heart muscle was replaced with fat. Before the accumulation of fat had occurred, there were cellular changes in the heart cells, including the dysregulation of calcium levels and action potential duration. Later, the team found that the drug istaroxime recovered these cellular dysfunctions of the heart. The findings were published in Nature Communications earlier this month. Kamel followed up on this animal model with transcriptomic analysis, which can be of potential help in the future to identify the molecular mechanisms of ACM and eventually therapeutics that tackle the specific aspects of the mechanism.

Organ dysfunction

Last but not least, Kamel focused on cohesinopathies, a group of diseases caused by mutations in the cohesin complex. This complex is involved in cell division and when it does not function properly, it can cause organs to dysfunction. The researchers generated zebrafish with a mutation in a gene called Shugoshin-1 (SGO1), which is involved in regulating heart rhythm. Kamel and her colleagues found that similarly to humans carrying this mutation, the zebrafish showed lower heart rates but also suffered from visual defects. Further research into the mechanisms of this disease is necessary to identify the exact cause of these organ dysfunctions.

Highlights

Before starting her PhD trajectory, Kamel had already completed a master’s internship in the group of Jeroen Bakkers. “I was familiar with the institute, people and techniques, which helped me when I started my PhD. And it was a bit of a relief that my master’s project already yielded some good results; I didn’t start my journey completely empty-handed.”

All in all, she very much enjoyed the past years at the Bakkers lab and the journey was filled with highlights. “I won a travel award in my hometown of Toronto, where I presented my PhD research at the Zebrafish Personalized/Precision Medicine meeting in 2019. That was actually the last time I got to visit my family before the pandemic hit, so it was very special. I also really enjoyed working on the Phospholamban project. We almost gave up on it, until, one late evening in the lab, we discovered that we had actually made a patient-specific zebrafish model for ACM!” she says. The resulting publication in Nature Communications put the cherry on the cake.

Feedback and support

However, how great such a publication may be, Kamel advises starting PhD students to not worry too much about publishing when starting out. “Focus on having one or two projects that are giving good results and most importantly: select a lab where you will receive a lot of feedback and support. It will make your journey enjoyable and keep your motivation going. Then, the publications will eventually come too.”