Simulation of a Cell Reveals Underlying Foundation of Basic Cell Survival

Cells make up the basis of life in all organic creatures, either as prokaryotic single cellular organisms such as E. Coli, or complex, multicellular organisms such as birds, reptiles, humans, and many more. Even in these large organisms, there are countless forms of cells, each acting and behaving both individually and within a larger system. For cells to arrive at this level of sophistication, it had to evolve over hundreds of millions of years, slowly but surely gaining complexity and efficiency. Because of this, it has become an extremely difficult life form to understand and comprehend. Recently, a team of engineers at UIUC have created a computer-generated simulation of a true living cell. The digital representation holds data of DNA, gene transcription and translation, as well as protein and lipid membranes, which rapidly increases the rate of understanding of basic cell functions and allows us to modify cellular functions to create synthetic cells designed to behave and function in a desired manner.

Studying cellular systems through biological means can reveal numerous underlying functionality of the cell but tend to have a long experiment duration and tedious preparation. Numerous fields utilize simulations, on the other hand, to quickly identify and track processes in complex systems and gather data that would typically take multiple days, or even months to get. In this case, researchers used this concept to generate a complete cellular model that acts and behaves similarly to a biological system. The synthetic cell in this experimental design allows the researchers to see certain patterns that would normally be invisible in a cellular assay. The simulation can track each individual protein, mRNA, energy molecule, etc. and is an extremely robust way to mark novel biochemical pathways and to further evaluate how cells respond to stimulus. This enabled the researchers to rapidly test various types of modifications in the cell and determine how the addition or deletion of certain genes affected the overall health of the lifeform. To determine the minimum number of genes and the type needed, the simulation coded the cell to the edge of survival and death, letting the experimenters to see what genes were in use and how the cell manages to stay alive. This begs the question, what is this biological minimal cell and the genes active in it?

The minimal, simulated cell is a synthetic cell that contains only the bare minimum number of genes to survive. It is not found in nature, but can survive like a typical cell would, only constantly on the verge of life and death. These minimal cells provide invaluable information to researchers to better understand the foundation needed for life to exist. In years past, scientists have created such a synthetic cell, one that only contained 473 genes, in which they added to an empty cell hose and tracked its movement and behavior. The team at UIUC updated this pre-existing model by incorporating some more genes and making it more sustainable to study for an extended period. Unlike the original model, this new cell, called JCV-syn3A, has 493 genes, a mere eighth of the genes in E. coli. However, despite this modification, there are still 94 genes whose purpose remains unknown. An ideal way of studying JCV-syn3A is to render a digital simulation and perform numerous tests to identify the behavior of each of the 94 unknown genes.

Creating this digital cell proved to be a challenge, however, due to numerous obstacles. For instance, the simulation required a detailed and precise map of all the cellular components in physical space. In addition, it also needed an accurate description of all the internal proteins, its role, location, and concentration distribution throughout the cell. Once all of these were set and the foundation was laid out, the researchers coded biochemical pathways and the intricate interactions between each molecule, protein, gene, energy molecule, and many more components. The final simulated cell provided a comprehensive model of each individual interaction with every possible cellular component. To check the validity of the newly simulated cell, they ran simulations alongside the JCV-syn3A cell and observed for any differences between the two. The simulated cell and its biological replica behaved in identically, enabling further research into potential modifications of the synthetic cell through the means of the simulated model. This digital cell showed the team how the cell distributes proteins, manages its energy consumption and production, as well as the production and degradation times of mRNA molecules based on their lengths. Changing the genome in both the digital and synthetic cell caused similar responses, one such being a 12-13% decrease in time between cell divisions.

Although the simulation provided great insights into the inner workings of a cell, it is not a perfect summary of how a biological system functions. There still lie many shortcomings in the simulated model, such as mechanical forces exerted on the cell by the ECM, even minute interactions on an atomic scale, as well as the physics of cell-cell interaction in tissues. Nonetheless, the current model was a tremendous step forward in synthetic biology and understanding how each individual component of a cell contributes to its overall health and function. Future studies can hopefully generate even more robust models of cells and perhaps even tissues, revealing more underlying cell machinery and behavior.

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