Detailed 3D Simulation of a Living Human Cell

Scientists report that they have built a living “minimal cell” with a genome stripped down to its barest essentials – and a computer model of the cell that mirrors its behavior. By refining and testing their model, the scientists say they are developing a system that can predict how changes to the genomes, living conditions or physical characteristics of live cells will alter how they function.

The simulation maps out the precise location and chemical characteristics of thousands of cellular components in 3D space at an atomic scale. It tracks how long it takes for these molecules to diffuse through the cell and encounter one another, what kinds of chemical reactions occur when they do, and how much energy is required for each step.

To build the minimal cell, scientists at the J. Craig Venter Institute in La Jolla, California, turned to the simplest living cells – the mycoplasmas, a genus of bacteria that parasitize other organisms. In previous studies, the JCVI team built a synthetic genome missing as many nonessential genes as possible and grew the cell in an environment enriched with all the nutrients and factors needed to sustain it. For the new study, the team added back a few genes to improve the cell’s viability. This cell is simpler than any naturally occurring cell, making it easier to model on a computer.

The simulations gave the researchers insight into how the actual cell “balances the demands of its metabolism, genetic processes and growth,” Luthey-Schulten said. For example, the model revealed that the cell used the bulk of its energy to import essential ions and molecules across its cell membrane. This makes sense, Luthey-Schulten said, because mycoplasmas get most of what they need to survive from other organisms.

The simulations also allowed Thornburg to calculate the natural lifespan of messenger RNAs, the genetic blueprints for building proteins. They also revealed a relationship between the rate at which lipids and membrane proteins were synthesized and changes in membrane surface area and cell volume.

“We simulated all of the chemical reactions inside a minimal cell – from its birth until the time it divides two hours later,” Thornburg said. “From this, we get a model that tells us about how the cell behaves and how we can complexify it to change its behavior.”

“We developed a three-dimensional, fully dynamic kinetic model of a living minimal cell,” Luthey-Schulten said. “Our model opens a window on the inner workings of the cell, showing us how all of the components interact and change in response to internal and external cues. This model – and other, more sophisticated models to come – will help us better understand the fundamental principles of life.”

Cell Journal – Fundamental behaviors emerge from simulations of a living minimal cell

Highlights
• 3D spatial resolution of a fully dynamical whole-cell kinetic model
• Detailed single-reaction, single-cell accounting of time-dependent ATP costs
• Genome-wide mRNA half-lives emerge from length-dependent kinetics and diffusion
• Connections among metabolism, genetic information, and cell growth are revealed

Summary
We present a whole-cell fully dynamical kinetic model (WCM) of JCVI-syn3A, a minimal cell with a reduced genome of 493 genes that has retained few regulatory proteins or small RNAs. Cryo-electron tomograms provide the cell geometry and ribosome distributions. Time-dependent behaviors of concentrations and reaction fluxes from stochastic-deterministic simulations over a cell cycle reveal how the cell balances demands of its metabolism, genetic information processes, and growth, and offer insight into the principles of life for this minimal cell. The energy economy of each process including active transport of amino acids, nucleosides, and ions is analyzed. WCM reveals how emergent imbalances lead to slowdowns in the rates of transcription and translation. Integration of experimental data is critical in building a kinetic model from which emerges a genome-wide distribution of mRNA half-lives, multiple DNA replication events that can be compared to qPCR results, and the experimentally observed doubling behavior.

They provide the time-dependent information about the dynamic rates of genetic information processes, the 148 known metabolites, 452 proteins and mRNAs, 29 tRNAs, 503 ribosomes, and DNA undergoing over 7,000 reactions. With its reduced genome of 543 kbp and 493 genes, the minimal cell JCVI-syn3A has retained only a few genes for regulatory proteins and functional small RNAs.