Simulating the complete life cycle of a minimal bacterial cell in 4D (space and time)—from DNA replication to protein translation to metabolism and cell division—at nanoscale resolution has recapitulated how every molecule within that cell behaved over the course of a full cell cycle.
A new study presents a whole-cell spatial and kinetic model for the ∼100 min cell cycle of the living “minimal cell” developed at the J. Craig Venter Institute in California. The genetically minimal bacterium JCVI-syn3A is a modified bacterium with a pared-down genome that carries only the genes needed to replicate its DNA, grow, divide and perform most of the other functions that make life possible.
“This is a three-dimensional, fully dynamic kinetic model of a living minimal cell that mimics what goes on in the actual cell,” notes Zan Luthey-Schulten PhD, chair in chemistry at the University of Illinois Urbana-Champaign (UIUC). “Such a comprehensive undertaking was only possible through the combined efforts of a host of collaborators at the U. of I. as well as Harvard Medical School, where we systematically modeled the essential metabolism and other subcellular networks through a series of publications starting in 2018.”
This work is published in Cell in the paper, “Bringing the genetically minimal cell to life on a computer in 4D.”
The Syn3A cell has fewer than 500 genes, all of which reside on a single circular strand of DNA. The team generated experimental data that allowed accurate simulation and validation of numerous aspects of cell function.
“Most importantly, their work revealed the extent of DNA replication and that Syn3A’s cell division is symmetrical,” Luthey-Schulten said.
Like other bacterial cells, Syn3A has no nucleus. Every molecule that comprises and sustains it is either a component of its outer membrane, is transported into it from outside the cell or is assembled in the cytoplasm. The cell is so jam-packed with molecular players that, when creating high-resolution cartoons and animations of their computer simulations, the researchers had to render some of the components invisible. Making all the cellular proteins invisible, for example, allowed the scientists to see how Syn3A’s chromosome threads through the cell’s crowded interior.
Some processes were more computationally expensive than others, the team discovered. For example, they realized that chromosome replication was slowing the whole simulation to a crawl, nearly doubling the time it took to capture the whole cell cycle. They then determined that efficiently simulating the cell’s DNA replication process required its own dedicated graphics processing unit, while another GPU handled all other cellular dynamics. This allowed the team to simulate the full, 105-minute cell cycle in just six days of computer time.
They struggled with the challenge of simulating cellular events occurring at the same time in various parts of the cell. “I can’t overstate how hard it is to simulate things that are moving—and doing it in 3D for an entire cell was … triumphant,” said Zane Thornburg, PhD, a postdoctoral fellow at the Beckman Institute for Advanced Science and Technology and the Cancer Center at Illinois. “One of the last big hurdles that Andrew and I had to solve was understanding how the membrane and the DNA talk to one another when both are moving.”
While the simulated cell cycle has its limitations—this was not an atom-by-atom simulation but instead averaged the dynamics of individual molecules—it yielded a surprisingly accurate accounting of the timing of cellular processes. In repeated simulations involving individual cells with slightly varying start conditions, the simulated cell cycle occurred, on average, within two minutes of the real-world cell cycle, Thornburg said. The work was repeatedly guided and tested against actual experimental outcomes, a process that allowed the scientists to refine their simulations.
The ability to accurately capture the ever-changing conditions within a living cell opens a new window on the foundations of living systems, Luthey-Schulten said. “We have a whole-cell model that predicts many cellular properties simultaneously,” she said. “If you want to know what’s going on, say, in nucleotide metabolism, you can also look at what’s going on in DNA replication and the biogenesis of ribosomes. So the simulations can give you the results of hundreds of experiments simultaneously.”
The post Simulating Life: 4D Whole-Cell Model of a Minimal Bacterium appeared first on GEN – Genetic Engineering and Biotechnology News.
