Control of cytoplasmic viscosity
The cytoplasm is crowded with macromolecules. For a specific cell type, the macromolecular concentration is notably tightly controlled. Disruption of this balance can lead to cell senescence, hinder their growth, or impair mobility. But, how do cells sense and regulate their own cytoplasmic viscosity? And how is concentration homeostasis achieved? We made use of an undiluted cell-free cytoplasm, the Xenopus (African clawed frog) egg extract (see Chen*#, Huang* et al. (2023) ), which mimics the cytoplasm of embryonic cells. By altering the macromolecular concentration of the extract, we showed that the protein synthesis rate is more sensitive to changes in cytoplasmic viscosity than the degradation rate. This potentially offers a negative-feedback homeostatic system for protein concentration derived directly from sensing the physical properties of the cell.
We are delving deeper into this topic to discern what other biological processes are influenced by or contribute to cytoplasmic viscosity and to determin if certain proteins are more susceptible to cytoplasmic changes. Our aim is to grasp how cells intereact with their biophysical attributes, an emerging area of research bridging biology and physics.
Mechanisms of cellular aging
As cells age, they experience an array of changes: the cell volume increases, the cytoplasm becomes diluted, macromolecular damage accrues, transcription slows down, the cytosol acidifies, organelles deteriorate, energy levels decrease, and the cell cycle decelerates. But what sparks these shifts, and what are their repercussions? What mechanism connects these gradual alterations to the decisive move towards cell death? We address these queries using our favorite cytoplasm (from Xenopus) and model cells (budding yeast and human cells). By adjusting the cytoplasmic concentration as well as other factors, we probe how these elements influence the biochemical reactions and cellular functions related to aging. We are also exploring how cells perceive and respond to these shifts, and whether they can modulate them to forestall or avert senescence. Our research aims to elucidate the core principles of cellular aging and shed light on potential prevention and treatment strategies for age-related ailments.
Crosstalk between energy state and cell cycle progression
Our prior studies revealed that cells accumulate carbohydrates intentionally before cell cycle entry, particularly when sensing nutrient depletion ( Gang Zhao*, Yuping Chen*, et al., (2016) ). This carbohydrate storage and utilization is directly controlled by the central cell cycle signaling pathway. Additionally, the energy state of the cell, indicated by the ATP/ADP ratio, can influence the cell cycle, possibly via phosphorylation and dephosphorylation reactions dependent on these two substrates. Our unpublished data suggest that there might be two stages of cell cycle entry: one that prepares for daughter cell growth, and another that commits to the S-phase. Analyzing the processes involved in cell cycle entry will aid our understanding of the cell cycle machinery holistically and the role of energy flux in fueling the cell cycle's oscillations.
Towards synthetic biological functions and synthetic cells
We are captivated by life's diverse forms and yearn to engineer one. Yet, constructing synthetic life or even its basic unit, the cell, remains challenging. Cells are not tailored to maximize the speed of a specific reaction or a group of reactions (Chen*#, Huang* et al. (2023) ). This understanding suggests our attempts to establish a synthetic biological function or even a synthetic autonomous cell should address both systemic regulation and potential physical constraints a cell might face. Concurrently, a consistent Xenopus egg extract can autonomously organize into cell-like compartments, facilitating physiological functions that are otherwise absent. One potential approach to crafting a synthetic cell might involve deconstructing an existing one. We are collaborating with experts across membrane biology, biochemistry, biophysics, and synthetic biology, to scrutinize, deconstruct, construct, and ultimately evolve a synthetic cell.