How do cells measure time? NWO ENW-XL grant for consortium with three Hubrecht researchers.

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A group of researchers from the Hubrecht Institute, AMOLF, TU Delft and ENS Paris has received a 2.7 million euro ENW-XL grant from NWO to study how cells measure time. This project brings together experts from different fields, including Rik Korswagen, Jacques Bothma and Alexander van Oudenaarden from the Hubrecht Institute.

During the development of an embryo, each cell must divide and assume different fates at just the right time. In the brain, for example, it is important that certain types of nerve cells are formed earlier than others. Even later in life, such as at the onset of puberty, it turns out that the body has a way of registering time. But how does that work at the cellular level? “We know that time plays a crucial role in development, but how cells track time is largely unknown, mainly because these processes are difficult to track in most types of embryos” says developmental biologist Rik Korswagen.

Cells with a stopwatch

To unravel this, the researchers use the simple roundworm C. elegans. This animal has a transparent body consisting of only 959 cells. This allows researchers to closely follow the development of individual cells. Korswagen’s group discovered that a moving cell in a growing worm knows very precisely when to stop moving. They find this position not because of a molecular stop sign at the final destination, but simply because they know that time has run out. Now the researchers want to further unravel how this internal stopwatch works.

Expression of the timing protein LIN-39 (green) in C. elegans. Credit: Lucia Garcia del Valle Martinez, Copyright: Hubrecht Institute

The researchers suspect that cells measure time via protein gradients-guided changes in the concentration of regulatory proteins. Cells would start a process only when a particular protein reaches a critical value. But because proteins fluctuate naturally, it is unclear how this allows cells to maintain a precise timing mechanism.

An interdisciplinary collaboration

To answer this fundamental question, biologists, physicists and mathematicians are joining forces. By applying new biological techniques and theoretical concepts from physics, they can study cell timing in C. elegans.

“We can discover a lot with experiments, but without the models and techniques of our colleagues, we would never figure out how cells can build and read such a precise clock,” says Korswagen. “The strength of this consortium is that successive cycles of experiments, data analysis and mathematical models continuously reinforce each other.”

By combining different disciplines, such as precisely measuring gene expression dynamics (Jacques Bothma), determining where regulatory proteins bind in the genome (Alexander van Oudenaarden), understanding how perturbations affect the system (Marie-Anne Felix) and building mathematical models (Marianne Bauer and Jeroen van Zon), the researchers hope to answer the big question: How do cells measure time?

A better understanding of the mechanisms by which cells measure time is crucial for applications in regenerative medicine and important for our understanding of the origins of birth defects and other developmental diseases.

The team

Dr. J.S. van Zon (AMOLF), Dr. M.S. (Marianne) Bauer (TU Delft), Prof. Dr. A. (Alexander) van Oudenaarden (Hubrecht Institute), Prof. Dr. H.C. (Rik) Korswagen (Hubrecht Institute), Dr. J.P. (Jacques) Bothma (Hubrecht Institute), Prof. Dr. M.-A. (Marie-Anne) Félix (ENS Paris)