Most Complete Simulation of a Cell Probes Life’s Hidden Rules

From the bizarre creatures in the depths of the oceans to the bacteria inside our bodies, all life on Earth consists of cells. But we have only a very rough idea of how even the simplest of those cells function.

Now, as described recently in Cell, a team at the University of Illinois, Urbana-Champaign and their colleagues have created the most complete computer simulation ever of a living cell. With this digital model, biologists can burst through nature’s constraints and accelerate their exploration of how the most basic unit of life ticks — and what would happen if it ticked differently.

“Imagine being able from one simulation … to recover results that would take many, many experiments to do,” said the senior author, Zaida (Zan) Luthey-Schulten, who led the group conducting the simulations at the University of Illinois. Using the model, she and her colleagues have already made surprising discoveries about the physiology and reproductive cycle of their modeled cell, and the simulation continues to serve as an idea generator for further experiments.

“This is the first time we can have a really careful computational look into a metabolism of a whole complex system — not just a biochemical reaction or a very artificial system but an entire living cell,” said Kate Adamala, a synthetic biologist and assistant professor at the University of Minnesota who was not involved in the study. For years, scientists have tried to model entire cells and predict their biology accurately, but they’ve fallen short because most cells are too complex. “It’s hard to build a model if you don’t know what Lego bricks go into it,” Adamala said.

But the cell that the Illinois group is working with is so simple, with far fewer genes than any other cell, that its physiology is more easily plumbed, making it an ideal platform for a model.

The cell in question is a lab-made “minimal cell” that teeters on the line between life and non-life, carrying a limited number of genes, most of them necessary for survival. By replicating the known biochemical processes happening inside this very basic cell and tracking all the nutrients, waste, gene products and other molecules moving through it in three dimensions, the simulation brings scientists closer to understanding how the simplest life form sustains itself and reveals some of the bare-bones requirements of life.

The findings are a steppingstone to building models of natural cells that are more complex and significant. If scientists can eventually build an equally detailed simulation of the common intestinal bacterium Escherichia coli, for instance, “that would be an absolute game changer, because all of our biomanufacturing runs on E. coli,” Adamala said.

A Digital Life

The minimal cell the team modeled, JCVI-syn3A, is an updated version of one developed by synthetic biologists at the J. Craig Venter Institute and presented in Science in 2016. Its genome is designed after that of the very simple bacterium Mycoplasmas mycoides, but stripped of genes that the project’s scientists systematically determined were not essential for life. JCVI-syn3A gets by with a mere 493 genes, roughly half the number of its bacterial inspiration and only about one-eighth as many as E. coli has.

Though simple, the cell is still enigmatic. For example, no one knows what 94 of those genes do except that the cell dies without them. Their presence suggests that there may be “living tasks or functions essential for life that … science is oblivious to,” said John Glass, a co-author of the new study and the leader of the synthetic biology group at the Venter Institute, and part of the team that developed the minimal cell in 2016. With modeling, the researchers hope they can quickly start to unveil some of these mysteries.

To build the new model, the team at the University of Illinois took an abundance of findings from various fields and wove them together. They used flash-frozen, thin-sliced images of the minimal cell to position its organic machinery precisely. A massive protein analysis helped them sprinkle all the right known proteins inside, and a detailed analysis of the cell membrane’s chemical composition, provided by their co-authors at the Dresden University of Technology in Germany, helped them place molecules correctly on the outside. A thorough map of the cell’s biochemistry provided a rulebook for the interactions of the molecules.

As the digital cell grew and divided, thousands of simulated biochemical reactions occurred, revealing how every molecule behaved and changed over time.

The simulations mirrored many measurements of living JCVI-syn3A cells in culture. But they also predicted characteristics of the cells that hadn’t yet been noticed in the lab such as how the cell portions out its energy budget and how quickly its messenger RNA molecules degrade, a fact that critically affects researchers’ understanding of how the cell regulates genes.

Some of the most surprising discoveries concerned the speedy growth and division of JCVI-syn3A cells. The simulation showed that to divide as rapidly as it does, the cell needs an enzyme called a transaldolase — but none seems to be present. Either the cell has evolved a metabolic pathway that makes the enzyme unnecessary, or “we are left with the possibility that there is such an enzyme, but that it does not look like an ordinary transaldolase,” Glass said.

He and his team are planning experiments to search for this mystery molecule, while also continuing to test some of the model’s other predictions. They have already confirmed, for example, that they can shorten the time between cell divisions simply by adding genes for two nonessential enzymes.

Remaining Unknowns

Not all of the simulation’s data agreed with experimental data — and the model has important gaps, such as the unknown functions of 94 of the genes. What’s more, the model is a fundamentally biochemical one, but “to fully understand the cell, we need to sort of model all of the forces and interactions of every atom or molecule of the cell,” Glass said.

He is discussing a potential collaboration with Roseanna Zia, an associate professor of chemical engineering at Stanford University, to build biophysical models of JCVI-syn3A that would examine how physics drives interactions inside the cells.

Though every model has its shortcomings, “what they’re doing in this study is so difficult and it’s so ambitious,” said Elizabeth Strychalski, who heads the cellular engineering group at the National Institute of Standards and Technology and co-authored the 2016 minimal-cell paper.  “It’s almost like we’re limited more by what we can imagine than by what we can do.”

With a complete enough model, the researchers should be able to get creative: They can see what happens if they prune biochemical pathways, drop in extra molecules or set the simulation in a different environment. The results should give more insights into which processes cells need to survive — and which they don’t. They might even offer glimpses into what the very first cells required billions of years ago.

Luthey-Schulten and her team hope to use the model soon to probe deeper questions about the minimum principles of life. For now, though, they are sifting through the data that the model has already provided. “Just the achievement of being able to put this minimal cell onto a computer, bring it to life and start interrogating it is exciting enough,” Luthey-Schulten said.