In a mix of artificial cells, one kind (purple) makes and releases a fluorescent protein, which is received and trapped within a second kind (gray), turning those mimics green.

HENRIKE NIEDERHOLTMEYER

Biologists create the most lifelike artificial cells yet

No biologist would mistake the microscopic "cells" that chemical biologist Neal Devaraj and colleagues are whipping up at the University of California, San Diego (UCSD), for the real thing. Instead of the lipid membrane that swaddles our cells, these cell mimics wear a coat of plastic—polymerized acrylate. And although they harbor a nucleuslike compartment containing DNA, it lacks a membrane like a real cell's nucleus, and its main ingredients are minerals found in clay.

Yet these mock cells are cutting-edge, "the closest anyone has come to building an actual functioning synthetic eukaryotic cell," says synthetic biologist Kate Adamala of the University of Minnesota in Minneapolis, who was not part of the work. Like real cells, the spheres can send protein signals to their neighbors, triggering communal behavior. And as Devaraj and his team revealed in a preprint recently posted on the bioRxiv site, the "nucleus" talks to the rest of the cell, releasing RNA that sparks the synthesis of proteins. The artificial nuclei can even respond to signals from other cell mimics. "This may be the most important paper in synthetic biology this year," Adamala says.

Synthetic biologists have big dreams for artificial cells. Compared with simpler synthetic structures, such as the liposomes that are already being used to transport certain drugs in the body, they could be more sensitive to their environment and perform a greater variety of jobs. In the future, artificial cells may deliver drugs more precisely to their targets, hunt down cancer cells, detect toxic chemicals, or improve the accuracy of diagnostic testing. Arrays of interacting synthetic cells could form artificial tissues and smart materials that sense and adapt to their surroundings. As scientists struggle to devise cell facsimiles, they may also learn more about how life originated and overcame some of the same engineering challenges.

Performing some functions of a cell, such as manufacturing proteins and duplicating DNA, in isolation won't be enough. "If we are going to develop synthetic materials, we need to have the individual units cooperate," Devaraj says. Researchers had already devised synthetic cells that can communicate with each other by exchanging relatively small molecules such as sugars and hydrogen peroxide. However, Devaraj notes, many of the molecular signals in our bodies, including the hormone insulin and the cytokines that fire up our immune cells, are proteins and are typically much larger.

To make a more cell-like cell mimic, Devaraj and his colleagues stepped away from nature. Their latest pseudocells "look a little bit like natural cells, but they are made of completely artificial materials," says co-author Henrike Niederholtmeyer, a synthetic biologist at UCSD. The researchers used a silicon chip with microscopic fluid-filled channels to extrude tiny droplets that contain raw materials such as DNA, minerals from clay, and individual acrylate molecules. Ultraviolet light and chemical treatment spurred a porous membrane to form around each droplet. At the same time, the minerals and DNA inside the droplet condensed into a gel with the texture of a soft contact lens, creating a version of the nucleus, Devaraj says.

The result was a cell replica with new powers of communication. For some experiments, Devaraj's team equipped the nuclei of the cell mimics with DNA that encodes green fluorescent protein (GFP). They also outfitted some of their creations with a trap, a sticky stretch of DNA that captures GFP molecules. By adding a mixture of enzymes and other necessities for protein synthesis, such as ribosomes, to the fluid surrounding the ersatz cells, the investigators switched them on. This molecular machinery crossed the porous membrane, read the genetic information in the nucleus, and sparked synthesis of GFP.

The scientists then mixed cell mimics designed to produce GFP with receiver cells that couldn't make the marker themselves but did harbor the DNA trap for GFP. After 2 hours, receiver cells that were adjacent to senders were aglow, indicating that they had picked up the GFP message from neighbors. In a similar experiment, the team crafted mimics that released a different protein signal that switches on GFP synthesis in recipients. Like real cells, these cell mimics could communicate with nearby counterparts and stimulate them to produce proteins.

The imitation cells also displayed another lifelike attribute called quorum sensing, in which cells' behavior changes once they become abundant enough. This ability came to light when researchers tested solutions containing different densities of cell mimics, all of which released the activator of GFP synthesis and could make GFP as well when triggered. If a solution contained only a few of the synthetic cells, almost none turned green. After they reached a threshold density, however, nearly all of them lit up. Before they can begin to make GFP, the artificial cells apparently need to absorb a certain minimal amount of the activating protein from their surroundings.

The cell mimics are tough, remaining undamaged after 2 years in a freezer. Their durability may make them good environmental sensors—one of several applications for the structures that the UCSD team is now exploring. And Devaraj and colleagues hope to equip these or other synthetic cells with the ability to grow and divide.

Bioengineer Yuval Elani of Imperial College London is impressed with the design of the cell mimics. "The concept of using these nonbiological components is a powerful one." But the artificial components could also be a drawback for applications, he notes, if they prove incompatible with "natural" components making up artificial cells that other researchers are developing.