Growth is the hallmark of the living world. Splitting, budding, or birth, following growth in or on the body, is how living systems generally procreate.

In an article in the Proceedings of the National Academy of Sciences (“Kinematic self-replication in reconfigurable organisms“) scientists report a new form of self-perpetuation that has not been observed in any living organism before. This new form of procreation arises spontaneously over a few days in synthetic, mobile spheres of frog (Xenopus) skin cells.

The authors show synthetic multicellular assemblies can self-replicate by moving and compressing dissociated cells in their environment into functional copies of themselves in a manner reminiscent of molecular replication.

“We show that clusters of cells, if freed from a developing organism, can similarly find and combine loose cells into clusters that look and move like they do, and that this ability does not have to be specifically evolved or introduced by genetic manipulation,” the authors note.

Using artificial intelligence, Josh Bongard, PhD, professor of computer science at the University of Vermont, Michael Levin, PhD, professor, and chair at the biology department at Tufts University, and colleagues design multicellular assemblies that can delay the loss of the ability to replicate and perform useful work as a byproduct of the process of self-replication.

In addition to new insights into the conditions under with synthetic cellular assemblies replicate, the study suggests unique and useful traits and functions can be derived from synthetic organisms without selection or genetic engineering.

Levin says, “It reveals immense plasticity in the behavior of cell groups which suggests new approaches to regenerative medicine (controlling self-assembly of complex, functional organs) without genomic editing or transgenes. This plasticity will be exploited for future work in birth defects, traumatic injury, cancer, aging.”

The researchers isolate normal, genetically unmodified skin cells from the frog’s larvae and incubate the cells to synthesize motile, multicellular spheroidal organisms covered in cilia–hair-like extensions of the cell surface that facilitate movement. They then place these organisms in dishes with other dissociated frog skin cells.

The researchers observe the cilia-covered organisms move in the dish to sweep some cells together into a pile. The piled-up cells stick together and compact to become similar motile organisms themselves after five days. This development occurs only in the presence of a progenitor organism.

The authors use an artificial intelligence-based method to design self-replicative organisms. Computer simulations show that the synthetic swarms can adhere to wires, closing a circuit. According to the authors, the findings broaden researchers’ understanding of developmental plasticity.

Commenting on the experimental method used in this study, Levin says, “The basic approach of using machine learning to shape stimuli for cells liberated from their default context is a specific new approach being pioneered here.”

Surface tension preferentially models these reconfigurable organisms into ciliated spheroids. Douglas Blackiston, PhD, senior scientist at Allen Discovery Center at Tufts University, who performed the biological experiments in the work says “This shape turns out to be inefficient at collecting cells – generally it must spin in a tight circle, collecting cells in the center of the spiral motion.”

To improve the ability of the organisms to self-replicate, the team employs AI tools to identify more shapes that are better at piling cells. ‘C’ shaped synthetic organisms have a snowplow-like design, that allows them to capture and push cells more effectively.  The size of the progeny bears directly upon the number of self-replicative generations since each generation is smaller than the last.

Blackiston says, “Once the computer comes up with a design, I use a set of tools—a microcautery electrode, small glass needles, different forms of compression, and microscurgery forceps—to ‘build’ the computer blueprint from the living tissue.  There are limits to what I can make by hand, but I can get close to the computer simulation.”

In their future work, the researchers plan to build useful synthetic living machines for applications in vitro, in vivo and in the environment. The team intends to use these organisms for further explorations into morphogenesis to reveal insights that can be used for regenerating and bioengineering complex living structures.

Blackiston says, “We plan to further investigate environmental applications—for example, sensing or decontaminating environmental pollutants, and medical applications—for example, drug delivery, injury repair, regeneration, as well as improve our ability to control the behavior of the organisms.”

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