The new evolution experiments are starting to provide insights into how the smallest, simplest organisms might evolve — and how principles of evolution unite all forms of life, even genetic novelties developed in labs. “Increasingly, we are seeing evidence that this [minimal cell] is an organism that is not something bizarro and unlike the rest of life on Earth,” said John Glass, an author on the Nature study and the leader of the synthetic biology group at the J. Craig Venter Institute (JCVI) in California that first engineered the minimal cell.
What If We ‘Let It Loose’?
Just as 19th- and 20th-century physicists used hydrogen, the simplest of all the atoms, to make seminal discoveries about matter, synthetic biologists have been developing minimal cells to study the basic principles of life. That goal was realized in 2016 when Glass and his colleagues produced a minimal cell, JCVI-syn3.0. They modeled it after Mycoplasma mycoides, a goat-dwelling parasitic bacterium that already gets by with a very small genome. In 2010, the team had engineered JCVI-syn1.0, a synthetic version of the natural bacterial cell. Using it as a guide, they drew up a list of genes known to be essential, assembled them in a yeast cell and then transferred that new genome into a closely related bacterial cell that was emptied of its original DNA.
Two years later at a conference in New England, Jay Lennon, an evolutionary biologist at Indiana University Bloomington, listened to a talk from Clyde Hutchison, a professor emeritus at JCVI who had led the team engineering the minimal cell. Afterward, Lennon asked him, “What happens when you let this organism loose?” That is, what would happen to the minimal cells if they were subjected to natural selection pressures like bacteria in the wild?
For Lennon as an evolutionary biologist, the question was an obvious one. But after he and Hutchison both pondered it for a few minutes, it became apparent that the answer wasn’t.
The minimal cell “is a type of life — it’s an artificial type of life, but it’s still life,” Lennon said, because it fulfills the most basic definition of life as something able to reproduce and grow. It should therefore respond to evolutionary pressures just as gorillas, frogs, fungi and all other organisms do. But the overarching hypothesis was that the streamlined genome might “cripple the ability of this organism to adaptively evolve,” Lennon said.
No one had a clue what would really happen, however, because researchers have generally taken great care to keep minimal cells from evolving. When samples of the cells are distributed by JCVI to any of the roughly 70 labs that now work with them, they’re delivered pristine and frozen at minus 80 degrees Celsius. When you take them out, it’s like their first day on Earth, Lennon said: “These are brand new cells that had never seen a day of evolution.”
Shortly after their encounter, Hutchison put Lennon in touch with Glass, who shared samples of his team’s minimal cells with Lennon’s lab in Indiana. Then Lennon and Roy Moger-Reischer, his graduate student at the time, got to work.
Testing the Streamlined Cells
They began with an experiment aimed at measuring mutation rates in the minimal cells. They repeatedly transferred a sliver of the growing minimal cell population into petri dishes, which freed the cells to grow without constraining influences like competition. They found that the minimal cell mutated at a rate comparable to that of the engineered M. mycoides — which is the highest of any recorded bacterial mutation rate.
The mutations in the two organisms were fairly similar, but the researchers noticed that a natural mutational bias was exaggerated in the minimal cell. In the M. mycoides cells, a mutation was 30 times more likely to switch an A or a T in the genetic code for a G or a C than the other way around. In the minimal cell, it was 100 times more likely. The probable explanation is that some genes removed during the minimization process normally prevent that mutation.
In a second series of experiments, rather than bringing over a small group of cells, the researchers transferred dense populations of cells for 300 days and 2,000 generations. That allowed more competition and natural selection to occur, favoring beneficial mutations and the emergence of genetic variants that eventually ended up in all the cells.
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