Thesis defense Louk Timmer: ‘Merging Macro and Micro: Transcriptional landscapes and in-depth studies for understanding heart disease’

The heart and heart failure
The heart is one of the most important organs in the body. It pumps blood that carries oxygen and nutrients to all cells. In heart failure, this pumping function deteriorates. This is a serious condition that reduces quality of life and increases the risk of death. Heart failure affects 1-3% of people in Western countries, significantly impacting society. Cells in a heart with heart failure function differently than those in a healthy heart, which can be due to differences in gene expression.

What is gene expression?
Although all cells have the same DNA, the activity of specific genes varies per cell. The activity of a gene is called gene expression. This allows, for example, heart muscle cells and liver cells to have different functions despite having the same DNA. However, gene expression can also differ in healthy and diseased cells. In diseases like heart failure, certain genes may become more or less active. These changes in gene expression can cause cells to function differently, contributing to the disease.

A dataset of gene expression
Timmer investigated gene expression during the recovery process after a heart attack in mouse hearts. “We used single-cell RNA sequencing,” says Timmer, “This is a modern technique that allows us to precisely observe changes in gene expression per cell.” Timmer and colleagues created a large dataset from the obtained data. “In the dataset, we could for instance see how heart cells communicate with each other. This allowed us to specifically observe a protein important for communication before and after a heart attack. The dataset can therefore be used to decipher new biology.”

Protein that reduces heart function
Using the dataset and those from other independent studies, Timmer and his fellow researchers found that the gene for the SORBS2 protein plays a role in heart failure. “Previously, SORBS2 was a relatively ill-studied protein,” says Timmer, “However, we discovered that this gene is more active in a heart with heart failure than in a healthy heart, both in humans and mice.” The researchers found that SORBS2 plays a role in the formation of connective tissue in the heart, which can further impair heart function.

Other scientists can now build on Timmer’s dataset, which could contribute to finding new treatment options. “Ultimately, I hope that patients with heart disease will benefit from the research in my dissertation.”

A PhD is hard work, but rewarding
“It was an incredibly inspiring journey, full of hard work but with much joy, also thanks to the pleasant collaboration with colleagues,” says Timmer. When asked about a highlight of his PhD, Timmer responds: “The moment you receive your results after waiting with curiosity. Also, the inspiration you get from conferences and scientific meetings.” Of course, there were also challenges: “It was difficult to decide when to stop optimizing an experiment when it didn’t go according to plan. When is it better to put your effort elsewhere?” His advice to future PhD students: “There is so much scientific knowledge: don’t neglect those published treasures, but use them to your advantage. If you are intrinsically curious and have a problem-solving mindset, I definitely recommend pursuing a PhD.”