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Cells with a stripped genome had a variety of inappropriate sizes (left) until scientists added seven genes and reverted to their normal shape (right).
JF Pelletier et al., Cell (2021) 184, 1-11
By Mitch Leslie
Five years ago, the researchers announced with great fanfare that they had designed a stripped microbial cell capable of surviving on fewer genes than any known organism. But this “minimal cell” often divides abnormally. Now, by putting in just seven genes, a team has corrected the cells to develop like the natural versions.
The discovery could sharpen scientists’ understanding of crucial functions for normal cells and what the many mysterious genes in these organisms do, says synthetic biologist Kate Adamala of the University of Minnesota, Twin Cities. “This is an important step forward that can perhaps help identify the functions of these unknown genes.”
Identifying essential genes could also benefit synthetic biologists, who work to make cells or cell-like objects that could produce chemicals, detect environmental conditions, administer drugs, and perform other tasks in the cell. industry and medicine. “We need to know what is the minimum list of parts that we need to put in place to restore life,” says microbiologist Anthony Vecchiarelli of the University of Michigan, Ann Arbor. Minimal cells could also provide insight into the origin of life by shedding light on essential capacities for primordial cells.
Genome sequencing pioneer J. Craig Venter of the J. Craig Venter Institute (JCVI) and his colleagues created the first minimal cells. They started with Mycoplasma microbes, parasites that are already pretty minimal – one strain gets by with 525 genes, compared to around 4,000 of the common gut bacteria Escherichia coli. In 2010, the team reported that replacing the genome of the 985 gene from a type of Mycoplasma with a synthetic genome of the 901 gene kept the cell, nicknamed syn1.0, purring. Scientists continued to remove pieces of DNA from the syn1.0 genome, and in 2016 they unveiled an even more sparse version known as syn3.0 that could metabolize and reproduce with a meager 473 Genoa.
But this cell also has a peculiarity: a large part of its offspring is deformed. To test whether lab conditions could stress delicate synthetic cells, a group led by synthetic biologist Elizabeth Strychalski of the National Institute of Standards and Technology pampered the cells in chambers on microfluidic chips. These luxury quarters shielded cells from currents in the nutrient medium that could harm them and allowed researchers to watch as they divided.
This gentle treatment didn’t make a difference, however. “When we looked at the level of single cells, it was absolute chaos,” says Strychalski, who has worked with colleagues from JCVI and three universities. The cells should have been small orbs, but some were behemoths about 25 times the normal circumference. Others looked like threads or strings of pearls. Rough handling was not the problem, the researchers concluded; instead, the problem was with the removal of genes that help control reproduction and cell shape.
It wasn’t clear which missing genes were to blame, but a clue lay in a lab freezer. To create syn3.0, Venter and his colleagues generated a variety of other cell strains lacking parts of the syn1.0 genome. When Strychalski and his team thawed one of these strains, which lacked 76 of the syn1.0 genes, it also produced abnormally shaped offspring. “It helped us reduce genes from 400 to 76,” says co-author James Pelletier, a biophysicist at the Massachusetts Institute of Technology.
By adding combinations of genes to determine if the resulting cells were dividing normally, the researchers reduced the required number to 19, and then even more. Today in Cell, they report that they could restore normal division by adding just seven genes to syn3.0.
Two of the genes were already known to play a role in cell division, but the involvement of the other five came as a surprise – and their role in the cleavage of microbes remains unknown. The corrected minimal cells could help elucidate this still mysterious process, says Strychalski: “We still don’t know the mechanism by which these things divide. It turns my mind upside down – it’s one of the fundamental aspects of life. “
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