Researchers at Tufts University and Harvard University’s Wyss Institute have created tiny biological robots they call Anthrobots from human tracheal cells that can move on a surface and have been found to encourage the growth of neurons in an area of damage in a lab dish.
The multicellular robots, ranging in size from the width of a human hair to the point of a sharpened pencil, were engineered to self-assemble and were shown to have a remarkable therapeutic effect on other cells. The discovery is a starting point for the researchers’ vision of using patient-derived biobots as new therapeutic tools to regenerate, treat and cure disease.
The work follows on from previous research in the laboratories of Michael Levin, Vannevar Bush, Professor of Biology at Tufts University School of Arts & Sciences, and Josh Bongard at the University of Vermont, where they created multicellular biological robots from embryonic frog cells called Xenobots, capable of navigating passages, collecting materials, recording information, healing from injury and even playing for a few rounds on their own. At the time, researchers didn’t know if these abilities depended on them coming from an amphibian embryo or if biobots could be made from cells of other species.
In the current study, published in Advanced ScienceLevin, along with PhD student Gizem Gumuskaya discovered that the bots can actually be created from adult human cells without any genetic modification and exhibit some abilities beyond what was seen with the Xenobots. The discovery begins to answer a larger question posed by the lab — what are the rules that govern how cells assemble and work together in the body, and can cells be removed from their natural context and recombined into different ones? body designs” to perform functions other than design?
In this case, the researchers gave human cells, after decades of quiet life in the trachea, a chance to reboot and find ways to create new structures and tasks. “We wanted to explore what cells can do besides create default features in the body,” said Gumuskaya, who earned a bachelor’s degree in architecture before majoring in biology. “By reprogramming the interactions between cells, new multicellular structures can be created, analogous to the way stone and brick can be arranged into different structural elements, such as walls, arches or columns.” The researchers found that not only could the cells form new multicellular shapes, but they could move in different ways over a surface of human neurons grown in a lab dish and encourage new growth to fill in the gaps caused by the scraping of the cell layer.
Exactly how the Anthrobots encourage neuron growth is not yet clear, but the researchers confirmed that neurons grew under the area covered by a clustered set of Anthrobots, which they called a “superbot.”
“The cell assemblies we make in the lab can have abilities that go beyond what they do in the body,” said Levin, who also serves as director of the Allen Discovery Center at Tufts and is a member of the Wyss Institute faculty. “It is exciting and completely unexpected that normal patient tracheal cells, without modifying their DNA, can move on their own and encourage the growth of neurons in an area of damage,” said Levin. “Now we’re looking at how the healing mechanism works and asking what else these constructs can do.”
Advantages of using human cells include the ability to make bots from the patient’s own cells to perform therapeutic work without the risk of provoking an immune response or requiring immunosuppressants. They only last a few weeks before breaking down, so they can easily be reabsorbed into the body after they’ve done their job.
Furthermore, outside the body, the Anthrobots can only survive in very specific laboratory conditions and there is no risk of exposure or accidental spread outside the laboratory. Likewise, they do not reproduce and have no genetic modifications, additions or deletions, so there is no risk of them evolving beyond existing safeguards.
How are Anthropots made?
Each Anthrobot begins as a single cell, derived from an adult donor. The cells originate on the surface of the trachea and are covered with hairy projections called cilia that wave back and forth. Cilia help cells in the trachea push out tiny particles that find their way into the air passages of the lung. We all experience the work of cilia cells when we take the final step of expelling particles and excess fluid by coughing or clearing our throat. Previous studies by others have shown that when cells are grown in the lab, they spontaneously form tiny multicellular spheres called organoids.
The researchers developed growth conditions that encouraged the cilia to face outwards in the organelles. Within a few days they began to move around, driven by the cilia which functioned as oars. They noted different shapes and kinds of movement — the first. important feature observed in the biorobotics platform. Levin says that if other features could be added to the Anthrobots (for example, contributed by different cells), they could be designed to respond to their environment and travel and perform functions in the body or help build mechanical tissues in the laboratory.
The team, with the help of Simon Garnier at the New Jersey Institute of Technology, characterized the different types of Anthrobots being produced. They observed that bots fall into a few distinct categories of shape and motion, ranging in size from 30 to 500 micrometers (from the thickness of a human hair to the point of a sharpened pencil), filling an important niche between nanotechnology and larger mechanical devices. .
Some were spherical and completely covered with cilia, and others were irregular or football-shaped with more patchy cilia coverage or only covered with cilia on one side. They traveled in straight lines, moved in tight circles, combined these movements, or simply sat and swayed. The globules fully covered with cilia tended to be flickering. Anthrobots with unevenly spaced cilia tended to move forward for longer distances in straight or curved paths. They typically survived about 45-60 days in laboratory conditions before biodegrading naturally.
“Anthrobots self-assemble in the lab dish,” said Gumuskaya, who created the Anthrobots. “Unlike Xenobots, they don’t need tweezers or scalpels to shape them, and we can use adult cells — even cells from elderly patients — instead of fetal cells. It’s fully scalable — we can produce swarms of them robots in parallel, which is a good start for developing a therapeutic tool.”
Because Levin and Gumuskaya eventually plan to build Anthrobots with therapeutic applications, they set up a lab test to see how the robots could heal wounds. The model involved growing a two-dimensional layer of human neurons, and by simply scratching the layer with a thin metal rod, they created an open cell-free “wound.”
To ensure that the void would be exposed to a dense concentration of Anthrobots, they created “superbots” a cluster that naturally forms when Anthrobots are confined to a small space. The super robots consisted mostly of circlers and shakers so they wouldn’t wander too far from the open wound.
While it might be expected that genetic modifications of the Anthrobot cells would be needed to help the robots encourage neural growth, surprisingly the unmodified Anthrobots induced significant regeneration, creating a bridge of neurons as thick as the rest of the healthy cells in the dish. Neurons did not grow in the wound where the Anthrobots were absent. At least in the simplified two-dimensional world of the lab dish, the Anthrobot assemblies encouraged the efficient healing of living neural tissue.
According to the researchers, further development of the robots could lead to other applications, including clearing plaque buildup in the arteries of patients with atherosclerosis, repairing damage to the spinal cord or retinal nerve, identifying bacteria or cancer cells, or delivering drugs. in targeted tissues. The Anthrobots could theoretically help heal tissues while also injecting regeneration drugs.
Creating new blueprints, restoring old ones
Gumuskaya explained that cells have the innate ability to self-assemble into larger structures in some fundamental ways. “Cells can form layers, fold, make spheres, sort and divide by type, merge with each other or even move,” Gumuskaya said. “Two major differences from inanimate bricks are that cells can communicate with each other and build these structures dynamically, and each cell is programmed with many functions, such as movement, secreting molecules, detecting signals, and more. We just understand how to combine these elements to create new biological body designs and functions — different from those found in nature.”
Harnessing the inherently flexible rules of cell assembly helps scientists build robots, but it can also help them understand how natural body blueprints are assembled, how the genome and environment work together to create tissues, organs and limbs, and how to restore them with regenerative treatments.