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Microbial Mules: Engineering Bacteria to Transport Nanoparticles and Drugs

Bacteria are exquisite living machines that could one day deliver medicine to cells in the human body, if scientists overcome the numerous obstacles
e-coli-bacteria



Mattosaurus, Wikimedia Commons

Tiny robots that swim through our blood vessels attacking viruses and malignant cells have not quite crossed the line that separates science fiction from science—but there might be a way to jump-start their development.

Engineering nimble robots that are smaller than blood cells is extremely challenging. Rather than design them from scratch, some scientists have been experimenting with the idea of enlisting an army of sophisticated nanobots already at our disposal: the thousands of species of bacteria swarming inside our bodies right now. In recent years researchers have saddled microorganisms with useful nanoparticles and bits of DNA. Although the research is preliminary, some engineers and microbiologists see realizable potential. This week, at the American Chemical Society's annual meeting in San Diego, biomolecular engineer David Gracias of Johns Hopkins University discussed the progress he and his colleagues have made in gluing nanoparticles to bacteria.

So far, Gracias and his colleagues have managed to decorate Escherichia coli with incredibly tiny beads, rods and crescents made from nickel and tin coated in gold. Each nanoparticle is about 300 nanometers in diamter, or three times the size of a particle of wood smoke. The researchers stuck the nanoparticles to the bacteria with antibodies, which are small, Y-shaped proteins that the immune system uses to identify foreign cells, viruses and harmful bacteria. Each antibody fits like a puzzle piece into an array of different proteins on the surfaces of invading pathogens; antibodies can also lock onto other antibodies—usually from a different species. Gracias and his colleagues first coated the nanoparticles with antibodies from goats and rabbits, and subsequently coated the bacteria in complementary antibodies. When they soaked the bacteria in a solution of the nanoparticles and heated the mixture, the beads, rods and crescents stuck to the bacteria, like so many Lucky Charms marshmallows clinging to the underside of a wet spoon.

Gracias and his teammates also devised a way to load bacteria with nanoparticles at tiny docking stations and release them on demand. First they covered small squares of silicon and gold with a field of Y-shaped antibodies, to which they attached small beads dotted with complementary antibodies. Then they introduced bacteria sporting another set of complementary antibodies to the awaiting beads—as expected, they clasped like Velcro. A wave of dissolving chemicals detached the bacteria and their cargo beads from the docking station.

Many bacteria saddled with nanoparticles were still able to move around freely, albeit not as quickly as their unencumbered brethren. Sometimes, though, the backpacking bacteria just spun in circles, apparently unable to move forward. "This is definitely a work in progress," Gracias says. "Right now we are mostly focusing on varying the size and shape of the nanoparticles and making sure they stick."

Such nanoparticles can be heated from afar with infrared light, destroying diseased tissue. Ultimately, Gracias dreams of coaxing bacteria to ferry spongy nanoparticles soaked in drugs and outfitting bacteria with tiny sensors that measure local temperature and pH or tiny tools that perform surgery on a single cell. Similar research by other scientists confirms the potential of engineered bacteria to deliver medical packages directly into living cells.

In earlier work, Demir Akin of Stanford University and his colleagues used antibodies and nanoparticles to attach molecules of DNA to weakened Listeria monocytogenes, which is a bacterium responsible for many cases of food poisoning. L. monocytogenes is an intracellular bacterium, which means it has evolved ways to get inside animal cells. Akin attached a luciferase gene—which codes for the enzyme that makes fireflies glow—to L. monocytogenes and injected the germs into living mice. Three days later the mice glowed under a specialized camera, confirming that not only had the bacteria entered the mouse's cells, the cell nuclei had incorporated the bacteria's cargo and expressed the gene. Akin designed the living microbots to release their DNA packages inside mammalian cells, where the pH is low (acidic) enough to dissolve the chemical bonds gluing the luciferase gene to the bacteria.

The advantage of L. monocytogenes is that it knows how to get into cells, but it would be risky to use even a weakened version as a medical workhorse because it makes people sick. E. coli, in contrast, are much more harmless, but not all strains have specific adaptations for entering cells. The key, says Douglas Weibel of the University of Wisconsin–Madison, is working with a harmless microorganism that is a strong swimmer and has no problem butting its way into mammalian cells. In an experiment they conducted largely for fun, Weibel, George Whitesides of Harvard University and their colleagues yoked nanosize polystyrene beads to a single-cell green alga called Chlamydomonas reinhardtii. Weibel and Whitesides successfully steered their "microoxen" by shining light on one side of the algal cells (algae move toward light).

After that, Weibel did not pursue the challenge of engineering microorganisms to ferry nanoparticles, but he remains fascinated by the ongoing research. "Bacteria have already figured out how to move around in the body," he says. "They have evolved amazing motility. They can sense changes in their environment and adapt, not only on a short timescale, but they can adapt genetically, too. Even if we can't get them to deliver things in the human body, they could be useful for transporting nanoparticles in the lab. Who knows what advances we'll have 50 years from now."

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