13 June

Thesis defense Lotte Koopman: Fishing for genes – functional genetics of cardiac arrhythmias

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Lotte Koopman, from the group of Jeroen Bakkers at the Hubrecht Institute and the group of Teun de Boer at the UMC Utrecht, has successfully defended her thesis on the 13thof June. During her PhD, Koopman used the zebrafish to study genes that may be involved in cardiac arrhythmias in humans. This research resulted in her thesis “Fishing for genes – Using zebrafish to study the functional genetics of cardiac arrhythmias”.

Cardiac arrhythmias
Every year, millions of people die because of cardiac arrhythmias that result in sudden cardiac death. Sadly, we do not yet know enough about arrhythmias to bring this number down. This is mainly due to the complex underlying causes of arrhythmias. The research of Koopman therefore focussed on the identification of new genes that are associated with arrhythmias and the development of new research tools to study arrhythmias in more detail using the zebrafish.

Eye defects in the zebrafish GNB5 model

Zebrafish symptoms
One of the genes Koopman studied is a gene called GNB5. She decided to study this gene because a group of patients with cardiac arrhythmias and other symptoms had a mutation in this gene. She made a zebrafish model in which the GNB5 gene is defective, and found that these zebrafish have symptoms that are very similar to those of the patients: the zebrafish have a very slow heartbeat, problems with eye movement and problems with their muscles. This shows that the GNB5 mutations in the patients were indeed causing their symptoms. More detailed experiments, in which electrical signals of individual heart cells with the mutation were measured, showed that GNB5 is very important in controlling the process that brings the heart rate down during rest. When GNB5 is defective, there is no brake on this process and the heart rate becomes extremely low during rest. In the future, this model will be further characterized, and may also be used to screen drugs at a large scale, which could potentially help treat GNB5 patients.

Optogenetic tool that visualizes calcium in the zebrafish heart (ventricle on the left, atrium on the right.

Visualizing current
To study what happens in heart muscle cells during cardiac arrhythmias, Koopman and her colleagues used two so called optogenetic sensors and altered them so that they could be used in the zebrafish heart: one sensor to measure calcium, and one sensor to measure voltage. These optogenetic sensors are molecular tools that measure molecules or processes in individual cells (in this case calcium or voltage) and visualize these molecules or processes through a fluorescent signal that can be observed and tracked under the microscope. Calcium and voltage are two very important components of the heart and are involved in heart rhythm. Therefore, these optogenetic tools can help to further understand what exactly goes wrong in cardiac arrhythmia at the cellular level.

The zebrafish as a model
Koopman showed during her PhD that other genes associated with arrhythmias can be studied in a similar way using the zebrafish. “The zebrafish is a great organism to model cardiac arrhythmias,” says Koopman. “Normally the heart is very difficult to access due to its location within the thorax. The transparency of zebrafish embryos and larvae combined with the use of optogenetic tools makes it possible to study complex processes in the cells of the heart inside a living organism.”

During her PhD, Lotte Koopman was employed both at the Hubrecht Institute and the UMC Utrecht. She is currently using her expertise in her new function at Single Cell Discoveries, a Hubrecht Institute spin-off company that offers single cell sequencing as a service to other researchers, hospitals and companies.

 

 

Jeroen Bakkers is group leader at the Hubrecht Institute and professor of Molecular Cardiogenetics at the UMC Utrecht.

 

Teun de Boer is assistant professor at the Medical Physiology department of the UMC Utrecht.