In a lab at the University of Minnesota, a tiny blob eats, grows, competes, divides and replicates—nearly everything a living cell does. Called the SpudCell, its makers say it is the first synthetic cell to complete a full cellular life cycle. The announcement of the synthetic cell earlier this month was met with a mix of shock and awe, with many asking whether it could be deemed alive. But after just five generations, something in the SpudCell breaks—and some experts argue that perhaps it isn’t so close to life after all.
The SpudCell largely resembles a living cell, with a lipid membrane and a small genome, despite being stitched together from a list of nonliving ingredients. It can perform basic cellular functions, but it falls short of life. It needs a lot of outside help to keep going, and even then, it can’t maintain its life cycle for more than a few generations. The reason why may have to do with a crucial structure inside cells that is called the ribosome.
The ribosome is a cell’s “molecular machine,” explains Michael Jewett, a bioengineer at Stanford University, who was not involved in the SpudCell project. The ribosome is what translates genetic instructions to make proteins, which are themselves strings of amino acids that do nearly everything a cell needs done to survive and thrive. Another way to think about this, he says, is that if DNA is the cookbook and RNA is the recipe card, then the ribosome is the “chef” that makes the finished dish.
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The SpudCell has no chef. Its genome carries instructions for feeding, growth, copying and division but not for building ribosomes from scratch. Instead the cell borrows ribosomes from the bacterium Escherichia coli. Researchers deliver the E. coli ribosomes, along with lipids and nutrients, to the cell through tiny droplets, or liposomes.
These borrowed ribosomes keep SpudCells’ protein production going for a while. But after five rounds of division, they deteriorate to the point that the cells are “limping along a little bit,” explains Aaron Engelhart, a geneticist and cell biologist at the University of Minnesota, who worked on the project. “We’re not able to get them to undergo successive rounds of division and behave as they did in the beginning.”
Fluorescent microscopy of SpudCell – a synthetic cell assembled entirely from non-living chemical components – undergoing division.
Kate Adamala / Adamala Lab
Exactly why the cells falter is an open question. Jewett suggests dilution could be a culprit. As the synthetic cells grow and split, their ribosomes may be spread thin until “there’s insufficient amount of biological ‘chefs’ lying around to keep us going,” he says.
Faulty inheritance might also be the problem. Because SpudCells’ genome is split across several separate pieces of DNA rather than a single molecule, as in a real cell, some of the synthetic cells fail to inherit a complete set of genes. After five rounds, only about 30 percent of the cells have inherited a full copy of the original genome, according to the team’s findings, which were reported on the preprint server bioRxiv and have not yet been peer-reviewed. “We don’t know that every component is getting absolutely everything it needs through each round of division,” Engelhart says.
This might have to do with how the cells are organized. A living cell divides through “an exquisitely choreographed process,” Engelhart says. SpudCell splits through a much simpler mechanism, with the proteins crowding its membrane until the stress makes it peel into two.
The inside of a cell has “everything packed up against everything else” but in an organized way, Engelhart says. Reproducing that order is tricky “and also a really important piece of the puzzle,” he says. The SpudCell just doesn’t have that level of organization, meaning that when it divides, the pieces might be distributed haphazardly.
The SpudCell also can’t rebuild its ribosomes itself—it doesn’t have the genes to do so. Engelhart says that future work may see these genes included but that getting a ribosome to assemble from scratch is “a whole field in and of itself.” The team is working on building ribosomes from genetic instructions, a process that involves synthesizing the dozens of proteins and RNA strands involved and coaxing them to assemble in the right order.
Even if the SpudCell isn’t alive, it might not have to be fully self-sufficient to be useful. Jewett points out that there are plenty of applications, such as drug delivery and diagnostics, that don’t need a cell that fully rebuilds itself but could benefit from a facsimile like the SpudCell. Jewett points to a water test developed by his lab: This cell-free system is embedded with genetic programming that allows it to change color in the presence of contaminated water. From an engineering perspective, the system only needs to run its circuit once, not indefinitely, to do the task. “You don’t actually need a synthetic cell,” he says. “You actually just need to be able to capture or harness the biological processes of living organisms.”
“We’re pretty far away from something that’s fully self-replicating,” Jewett says. But being able to build cells from the ground up could help researchers truly understand what a cell is, he adds.
“To me, that is fascinating to imagine.”
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