Periodic Reporting for period 2 - ALLOCHRONY (Quantitative Investigation of Interspecies Differences in Developmental Tempo)
Reporting period: 2022-11-01 to 2024-04-30
Embryos of different animal species develop at different paces - Human embryonic development takes ~60 days while that of mice is 20 days. At each developmental stage, the order of developmental processes and the underlying mechanisms are largely conserved between the species, but the progression speed differs. The overarching goal of this study is to reveal the molecular causes of ‘allochrony’, interspecies differences in developmental tempo. For that, we use a stem cell-derived in vitro system to compare multiple species in a similar culture condition without having ethical challenges. The segmentation clock, oscillatory gene expression during early embryogenesis, can be recapitulated from human and mouse pluripotent stem cells. The oscillation period of the segmentation clock is known to be species-specific - Human and mouse periods are 5-6 hours and 2-3 hours, respectively. As we have previously shown that the period difference stems from slower biochemical reactions of the human segmentaion clock as compared with that of the mouse, our main strategy is to dissect the mechanism further. We also test the universality of the mechanism by comprehensively measuring biochemical reaction rates and expanding the number of animal species.
The ALLOCHRONY project consists of three parallel aims:
Aim 1 Systematic measurement approaches to reveal the cause of slower reactions in human cells.
Aim 2 Hypothesis-driven approaches to reveal the cause of slower reactions in human cells.
Aim 3 Organoid zoo to test the universality of the mechanism of allochrony.
Even though the primary aim of this study is to reveal fundamental principles of development, ALLOCHRONY will be the first step to manipulating and controlling the biological tempo for applications.
The ALLOCHRONY project consists of three parallel aims:
Aim 1 Systematic measurement approaches to reveal the cause of slower reactions in human cells.
Aim 2 Hypothesis-driven approaches to reveal the cause of slower reactions in human cells.
Aim 3 Organoid zoo to test the universality of the mechanism of allochrony.
Even though the primary aim of this study is to reveal fundamental principles of development, ALLOCHRONY will be the first step to manipulating and controlling the biological tempo for applications.
We made very good progress in all aims and published some results.
Aim 1: As proposed, we systematically measured the protein degradation rates of human and mouse presomitic mesoderm cells, the cells that display the segmentation clock, by using the Stable Isotope Labeling by Amino acids in Cell culture (SILAC) method. We are now analyzing the data and testing the obtained hypotheses.
Aim 2: As proposed, we measured the metabolic rates (i.e. glycolysis rate and mitochondrial respiration rate) in presomitic mesoderm cells of six mammalian species. Even though both metabolic rates showed species-specific values, there was no correlation between the measured metabolic rates and the segmentation clock periods across species (Lazaro et al, Cell Stem Cell, 2023). These results do not support the idea that species-specific metabolic rates fully explain the species-specific developmental time. However, we also found that chemical inhibition of metabolism affects the segmentation clock periods in many species. Aim 3: We developed a novel human organoid that periodically forms somite-like structures (Sanaki-Matsumiya et al, Nat Commun, 2022). This human ‘somitoid’ also recapitulates the oscillation of the segmentation clock, providing an ideal platform to study developmental time and morphogenesis. We also expanded the number of species (e.g. rabbit, marmoset monkey, cattle and rhinoceros), setting up the ‘stem cell zoo’ in the lab. The comparison across six species enabled us to find several scaling laws of the segmentation clock (Lazaro et al, Cell Stem Cell, 2023).
Both somitoid paper and stem cell zoo paper were covered by several media, including Science Daily, Quanta magazine, and the Scientist.
Aim 1: As proposed, we systematically measured the protein degradation rates of human and mouse presomitic mesoderm cells, the cells that display the segmentation clock, by using the Stable Isotope Labeling by Amino acids in Cell culture (SILAC) method. We are now analyzing the data and testing the obtained hypotheses.
Aim 2: As proposed, we measured the metabolic rates (i.e. glycolysis rate and mitochondrial respiration rate) in presomitic mesoderm cells of six mammalian species. Even though both metabolic rates showed species-specific values, there was no correlation between the measured metabolic rates and the segmentation clock periods across species (Lazaro et al, Cell Stem Cell, 2023). These results do not support the idea that species-specific metabolic rates fully explain the species-specific developmental time. However, we also found that chemical inhibition of metabolism affects the segmentation clock periods in many species. Aim 3: We developed a novel human organoid that periodically forms somite-like structures (Sanaki-Matsumiya et al, Nat Commun, 2022). This human ‘somitoid’ also recapitulates the oscillation of the segmentation clock, providing an ideal platform to study developmental time and morphogenesis. We also expanded the number of species (e.g. rabbit, marmoset monkey, cattle and rhinoceros), setting up the ‘stem cell zoo’ in the lab. The comparison across six species enabled us to find several scaling laws of the segmentation clock (Lazaro et al, Cell Stem Cell, 2023).
Both somitoid paper and stem cell zoo paper were covered by several media, including Science Daily, Quanta magazine, and the Scientist.
Regarding Aim 2, we are following up on the roles of metabolism in the segmentation clock and other developmental processes.