Although bacteria may form colonies and biofilms, they do not constitute multicellular lifeforms like, well, us. Bacteria lack the ability to coordinate the basics of multicellularity, which include intercellular communication, cell adhesion, and asymmetric cell division. If this ability could be engineered into bacteria, they would become wonderfully strange—a science fiction nightmare, perhaps, or more likely a synthetic biologist’s dream.

Each of these three basics of multicellular life has already been engineered into bacteria—separately, not as components of a controllable, coordinated system. Both intercellular communication and cell-cell adhesion technologies are available to module-minded synthetic biologists. And now, thanks to the efforts of scientists based at Rice University, the third puzzle piece—asymmetric cell division—has become available. How might all the puzzle pieces fit together in future research? The imagination reels.

The Rice scientists, led by synthetic biologist Matthew R. Bennett, PhD, have created a genetic circuit that can produce genetically distinguished cells of Escherichia coli as the bacterium divides. The circuit helps bacteria accomplish, in their own way, stem-cell-like differentiation. Properly controlled, the circuit can lead to diverse communities of microbes that exhibit complex, nonnative behaviors.

Whereas stem cells elegantly differentiate themselves via epigenetic mechanisms, engineered bacteria may resort to a relatively crude expedient—what the Rice scientists call asymmetric plasmid partitioning (APP). Details about APP appeared August 12 in the journal Nature Chemical Biology, in an article titled, “A synthetic system for asymmetric cell division in Escherichia coli.”

“We engineered an inducible system that can bind and segregate plasmid DNA to a single position in the cell,” the article’s authors wrote. “Upon cell division, colocalized plasmids are kept by one and only one of the daughter cells. The other daughter cell receives no plasmid DNA and is irreversibly differentiated from its sibling.”

The article’s first author, Sara Molinari, a graduate student at Rice University, first discovered how to force plasmids in E. coli to aggregate in a single cluster so they do not distribute homogeneously during cell division, but rather are inherited by only one of the two daughter cells. The plasmid-laden daughter cell remains identical to the progenitor cell, while its sibling becomes genetically distinct as it loses the genetic information present on the plasmids.

Next, the Rice scientists tied differentiation to motility. They found that they could use their system to achieve physical separation of genetically distinct cells. “Finally,” the scientists reported, “we characterized an orthogonal inducible circuit that enables the simultaneous asymmetric partitioning of two plasmid species, resulting in cells that have four distinct differentiated states.”

This work started, Molinari recalled, with the goal of creating materials that can sense and adapt to an environment. “We thought if we could mimic this feature of higher-order tissues, we would increase the robustness of our colonies and their ability to perform tasks,” she said. “The challenge was to engineer a population of bacteria that becomes something else whenever it’s needed.”

Molinari and her colleagues hit the jackpot on their first try with E. coli. “There was no canonical way to engineer asymmetrical cell division,” she said. “It was a crazy idea, and it magically worked the first time.

“But there was something we couldn’t completely figure out about the system,” Molinari noted. “It took two years to find out I made a cloning mistake when I got this protein and put it in my plasmid. I had randomly added 17 amino acids at the beginning of the protein, and that made the whole system work.”

With that knowledge, she proceeded to improve upon the hydrophobic proteins that cluster in cells while they bind to target plasmids, holding them in place.

Bennett noted natural processes either load enough plasmids into a cell to ensure some land in each daughter cell or actively pull plasmids into each of the new cells to ensure they remain identical. “We have shown we can outcompete those processes,” he asserted.

APP could turn simple organisms into complicated systems that enhance understanding of multicellular life. “We’re pretty good at designing bacteria,” Bennett pointed out. “We’ve been doing that for years now. I think the field has evolved to the point where we can do amazing things with bacteria and people are asking what else we can do.”

The new discovery suggests one possibility—the coordination of intercellular communication, cell adhesion, and asymmetric cell division—may be within reach. “If we can control all those things together, we can talk about engineering interesting multicellular lifeforms,” Bennett declared. “It starts to feel a bit like science fiction, for sure.”

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