14 March, 2022
Animal development is, in fact, nothing but time. From the cell cycle to the circadian rhythms, our own lives are composed of clocks across scales. Understanding the rules that determine how cells and organisms can precisely initiate and terminate processes at specified times and how do they modulate the rate at which they tick will help us explain when processes go awry, for example in tissue overgrowth or deficits. Moreover, differences in timing (heterochronies) are a major driver for evolutionary change.
Throughout the animal kingdom, the duration of development and lifespan vary hugely despite many species sharing equivalent sets of genes. For instance, development in the mouse lasts around 20 days whereas the same stages in human embryogenesis take the first 60 days of pregnancy to complete. Some species can even halt development for a time, which doesn’t appear to affect development or lifespan. Research in my lab is beginning to decipher the molecular mechanisms that might cause these timing differences across species and why they exist.
What do we know already?
Given that all cells have the same genes in the nucleus, where and when genes are activated determines the existence of different cell types in our body. How this occurs from the time of fertilisation fascinates me the most as a developmental biologist. I approached this question during my PhD by investigating the earliest stages of embryo development from fertilisation to implantation. As I worked on the topic, I found it fascinating that the very same events lasted only three days in mouse, whereas it took up to six days in human embryos.
Mouse and human developing embryos reach the blastocyst stage
at different times. Nuclei of the cells in the embryo are coloured
according to intensity.
During my postdoc, I decided to investigate how is time encoded in the genome. I reasoned that it would require finding a simplified model of embryo development that would allow us to unequivocally decipher the molecular mechanism behind these differences in timing across species. I established models where stem cell differentiated or were guided to become motor neurons from mouse and human embryonic stem cells and mimicked the differences in developmental timing observed in embryos. I found that the slower pace in human differentiation was due to a proportional decrease in the time of expression of a large number of genes. Molecularly, we identified that the human proteins are on average more stable than mouse proteins, and that these differences in protein half-lives (aka the time it takes for half the protein levels to degrade) could explain the observed differences in timing between mouse and human in computer simulations.
A new focus
Most cross-species comparisons have focused their analyses on transcriptome wide measurements of development or on the identification of distinct elements within gene regulatory networks to explain species-specific traits, but little attention has been paid to the role and regulation of protein dynamics.
The textbook view on protein stability is that the rates at which proteins are assembled and broke down is constant for each protein across animals. Now we know this is not necessarily true in development and across species with varying lifespans. The finding on the differences in the rates of protein degradation in each species is the basis of my future research plans at the Babraham Institute where I want to study the role of protein turnover (production and degradation) in the unresolved question of how species-specific timing is determined.
The difference in the duration of processes across species seems to be a constant feature of biology. Mammals differ more than 100-fold in maximal lifespan, yet we haven’t figured out yet why or how does this happen. One of the reasons why it is difficult to understand the molecular mechanisms behind biological timing is that the differences in timing might be a multifactorial problem and it is difficult to compare across a range of organisms. So far, there is no sign of a master gene controlling the speed of biological processes. Examples of animal clocks include counting mechanisms that progress at varying rates and often run in parallel without any apparent interaction with each other. Therefore, the goal of the developmental clock requires a deep understanding on how to integrate and synchronise the various clocks in the tissues. Finally, developmental timing could be a product of differences in metabolic rate or the final size of the organisms. So timing, size and energy consumption might be all features of the same biological process.
I plan to investigate which specific proteins show similar or divergent dynamics in mouse and human cells and their impact on timing. I will explore whether metabolic rate is responsible for the regulation of the cellular clocks and protein stability, and I want to develop novel comparative developmental and ageing models to investigate the molecular mechanisms behind timing in development and homeostasis. Moreover, I want to take one step further and I want to establish in vivo models to investigate biological timing. To do so, I am very happy I can count on the support at the Babraham Institute, especially of the Signalling and Epigenetics programmes as well as the Science Facilities.
Besides providing new discoveries on a fundamental question with implications across molecular, cell, organismal and evolutionary scales, my work could have broad practical applications. The identification of physiological mechanisms that modulate timing and its translation to stem cell models could be useful in regenerative medicine or to prevent ageing. For example, modulating the speed of development may facilitate the faster generation of neurons for transplantation upon spinal cord injury. The generation of mature human motor neurons from stem cells takes up to 15 weeks. If we can reduce the timescales to around six weeks, we will improve the efficiency of regenerative medicine strategies. In the field of ageing, long-lived species show slower protein turnover rates. Therefore, decelerating protein turnover may allow lifespan extension.
14 March 2022
By Teresa Rayon