Thesis defense Silke Lochs ‘Connecting the dots: Developing multimodal sequencing technologies to study gene regulation in single cells’

Mammalian development begins from a single fertilized egg. This egg divides multiple times, creating various cell types, each with unique functions and shapes. Even though all these cells contain the same DNA, they use specific genes at different times during development. This selective gene usage is controlled by so-called epigenetic mechanisms, which regulate gene activity without changing the DNA itself. These mechanisms ensure that cells develop correctly in order to perform their designated functions in various parts of the body.

Genetic blueprints determine development

Lochs’ PhD research aimed to investigate the process of how our genetic blueprint (the identical DNA in each cell) directs cellular development and function. To explore this, she developed and applied single-cell multimodal sequencing technologies. These advanced techniques allow scientists to measure multiple features of how our genes are regulated within one individual cell.

During her PhD, Lochs and her colleagues developed such a technology, named the MAbID technique, which measures multiple epigenetic markers in a single sample. This technology enables scientists to look at various signals that control gene activity all at once, rather than separately. She also used the scDam&T-seq technology to simultaneously study genetic activity and genome folding during brain development. These technologies, together with other methods, can help study cellular function and tissue organization. In the future, this information can benefit the treatment of various diseases.

Where is Waldo: DNA edition

In the final part of her PhD, Lochs started developing the Waldo genetic cell-barcoding strategy, in close collaboration with the Tanenbaum lab. This approach will enable scientists to combine gene activity measurements with microscopy techniques in living cells. By doing so, researchers can directly observe how changes in gene expression influence cellular structures and functions.

The techniques that Lochs worked with were not available before her PhD and now they can be used to study cellular function at a deeper level. Lochs explains: “Collectively, my PhD research is aimed towards uncovering the intricate mechanisms that govern how genes are regulated in both space and time during development.”

The PhD experience: good but challenging at times

Lochs is overall very happy with her PhD experience. Although challenging at times, her learning trajectory and general experience was positive. She says: “I loved working together with my incredibly talented and fun colleagues and I have become close friends with many of them. For me, the thrill of science is in finding new challenges and questions to solve every day and to keep pushing until it works or you obtained the results you were after.” Some of the highlights during her PhD were presenting her work at the Cold Spring Harbor Conference in the US and finally pressing the upload button for her thesis.

Lochs also acknowledges the pressure and competition that academic science comes with and that this can be quite stressful and challenging to tackle. However, she also feels like this is increasingly recognized in the field, with more and more people becoming aware of these problems, and is hopeful for future changes. She says: “Doing a PhD can be great, as you will probably never experience the same professional freedom anywhere else and you are constantly surrounded by great science and talented people! However, it will require personal sacrifices and can be demotivating at times, so it’s important to work on something you really like and you feel excited about pursuing!”