Different species have different time cycles, with larger animals (like humans) living longer and ‘slower’ than smaller ones (like mice).
To find out why, a group of scientists led by Miki Ebisuya at European Molecular Biology Laboratory – Barcelona (EMBL Barcelona) have reconstituted human and mouse stem cells in vitro to analyse why their segmentation clock, an oscillating biochemical process, takes about two hours in mice and five hours in humans.
Their results show the reason is in the individual cell’s environment and the speed of biochemical processes including protein degradation and delays in gene expression processes.
The devil is in the biochemistry
The researchers looked into a master gene called HES7, which plays a key role in the oscillation cycle in both mice and humans. They swapped the HES7 genes between human cells and mouse cells, hoping to see an exchange of the oscillation frequency between the two species, but to their surprise this did not happen.
The team then looked at the degradation rate of the HES7 protein. They observed that both the human and the mouse version of the HES7 protein were degraded more slowly in human cells than in mouse cells. They also saw that the time it took cells to translate the HES7 gene into protein was significantly different.
“We have shown it is the cellular environment in human and mouse cells that makes a difference in the biochemical reaction speeds, and thus in the time scales involved”
Miki Ebisuya (EMBL)
The study was the fruitful collaboration of Miki Ebisuya’s lab at EMBL with the Garcia-Ojalvo lab at the Department of Experimental and Health Sciences, Pompeu Fabra University (DCEXS-UPF), both of them institutions at the Barcelona Biomedical Research Park (PRBB) – as well as the RIKEN Center for Biosystems Dynamics Research and Kyoto University.
The laboratory led by Jordi García-Ojalvo has participated in making theoretical estimates and modeling. Specifically, they have adjusted the experimental observations to a mathematical model that calculates, at the numerical level:
- the half-life of the proteins and mRNA molecules involved in this biological clock
- the different time delays caused by protein production (transcription and genetic translation)
“This collaboration is an example of how mathematical models are important for understanding living systems”Jordi García-Ojalvo (DCEXS-UPF)
“Without the model, it would be difficult to link the molecular, microscopic properties to a behavior as macroscopic as the speed with which the vertebrae form in an animal”, concludes the scientist.
Matsuda et al. Species-specific segmentation clock periods are due to differential biochemical reaction speeds. Science 18 Sep 2020:Vol. 369, Issue 6510, pp. 1450-1455. DOI: 10.1126/science.aba7668