Biobots: life beyond death and new possibilities

Many scientists and engineers are interested in synthetic biology. Some of them are designing new types of cells. They have shown that the cells of several organisms can be converted into biological robots¹. They are making anthrobots using human cells that are able to self-assemble into small, hairy structures capable of moving by themselves. Some are making xenobots that are made from frog cells that have already died. They can perform many tasks usually reserved for living cells, such as being able to replicate themselves. Both types of these biobots last no more than 60 days. They biodegrade safely once they're dead. But it's unclear how these repurposed cells are able to live so long after their parent organism dies. We also don't know the extent of their ability to develop new functions postmortem.

This may seem scary, but the medical and therapeutic possibilities that could be unlocked by exploring these questions could truly improve human health and longevity. Anthrobots created from a human patient's own cells could be programmed to repair damaged cells, deliver drugs and remove cancer cells and tumors^2-4. Engineered anthrobots injected into the body could potentially dissolve arterial plaque in atherosclerosis patients and remove excess mucus in cystic fibrosis patients. Researchers at Tel Aviv University in Israel have developed micro-robots that can scan individual cells to tell whether they're healthy or not. These tiny cell inspectors can transport appropriate cells to a different location with the body. They can use electricity or a magnet to move cells to a desired location for subsequent genetic analysis. This makes them a potentially groundbreaking new tool for diagnosing diseases or delivering drugs to a chosen location. They were inspired to develop the micro-robots by the natural functions of other cells found in our bodies. The tiny robots can be used to select cancer cells and transport them.

This enables doctors to take samples or biopsies for medical diagnosis. The micro-robots can distinguish between healthy or dying cells and capture individual blood and cancer cells within a single bacterium. This significantly advances the fields of hybrid propulsion and navigation by electric and magnetic mechanisms. Moreover, these micro-robots can identify and capture a single cell for local testing or retrieval and transport to an external instrument. The researchers are also trying to develop micro-robots that can work inside the body. They hope that they could be used as effective drug carriers that can be precisely guided to the target. This can prevent undesirable side effects caused by drugs that are not so specific, such as many currently used chemotherapeutic drugs used to treat many types of cancer.

This research has led to a new understanding of life and death. As described previously in this journal, the autopoietic theory of life is that all forms of life make themselves. That is, plants, animals, fungi and even single cells have a membrane, skin, bark or other type of selective barrier. For individual animal cells, the cell membrane and almost everything inside of the cell are continuously being broken down and remade. Life is sustained by a network of production processes, in which the function of almost every component is to participate in the production or transformation of itself and the other components in the network.

Life and death are traditionally viewed as opposites. When a cell or an organism dies, it is no longer able to support the autopoietic network and stops making itself. Instead, dead cells are broken down by other cells, such as macrophages. However, the emergence in laboratories of new multicellular life-forms from the cells of a dead organism questions this duality. These biobots are able to be transformed into systems that have new functions after death^5-6.

In some ways, this duality has not existed for some time. For example, when organs are donated after a person dies, the organ can start working again as the cells inside of it become autopoietic systems in the new host. Organ donation highlights how organs, tissues and cells can continue to function even after an organism’s demise. To better understand this resilience, researchers are studying what happens within an organism after it dies. Some cells can be transformed when provided with nutrients, oxygen, bioelectricity or biochemical cues. They acquire new functions and abilities after death. While caterpillars undergo metamorphosis and become butterflies, there are organisms that seldom change in ways that are not predetermined. Tumors, orgonoids, and cell lines (like HeLa cells) can divide indefinitely in a Petri dish, but are not considered part of the third state because they do not develop new functions.

However, researchers found that skin cells extracted from deceased frog embryos were able to adapt to the new conditions of a Petri dish in a lab, spontaneously reorganizing into multicellular organisms called xenobots. These organisms exhibited behaviors that extend far beyond their original biological roles. They use their cilia (small, hair-like structures) to navigate and move through their surroundings. In contrast, cilia are typically used to move mucus living frog embryos. Xenobots are also able to replicate their structure and function without growing. This differs from more common replication processes that involve growth within or on the organism’s body. Researchers have also found that solitary human lung cells can self-assemble into miniature multicellular organisms that can move around. These anthrobots have new, emergent properties. They are not only able to navigate their surroundings but also repair both themselves and injured neuron cells located nearby.

This demonstrates the remarkable plasticity of cellular systems and challenges the idea that cells and organisms can evolve only in predetermined ways. The third state suggests that the death of organisms may affect how life transforms over time. Several factors influence the ability of cells and tissues to survive and function after an organism dies. These include environmental conditions, metabolic activity and preservation techniques. Different cell types have varying survival times. For example, human white blood cells die between 60 and 86 hours after a person's death.

Metabolic activity affects the survival and function of cells. Metabolically active that require a continuous and substantial supply of energy to maintain their function are more difficult to culture than cells with lower energy requirements. Preservation techniques such as cryopreservation can allow tissue samples such as bone marrow to function similarly to that of living donor sources. Inherent survival mechanisms also play a key role in whether cells and tissues can survive. For example, researchers have observed a significant increase in the activity of genes that are linked to controlling stress and supporting the immune system after an organism dies. Other important factors include trauma, infection and the time elapsed since death affect the viability of tissues and cells. In addition, age, health, sex and type of species affect cells after an organism dies. For example, it is very difficult to grow and transplant metabolically active islet cells that produce insulin in the pancreas, from donors to recipients. Researchers believe that autoimmune processes, high energy costs and the degradation of protective mechanisms could be the reason behind many islet transplant failures.

Researchers are trying to determine how these variables allow certain cells to continue functioning after an organism dies remains unclear. One hypothesis is that specialized channels and pumps embedded in the outer membranes of cells are very important. These channels and pumps produce electrical signals that allow cells to communicate with each other and execute specific functions such as growth and movement. This affects the structure of the cells that they become.

The extent to which different types of cells can undergo transformation after death is also uncertain. We already know that genes involved in stress and immunity are activated after death, along with changes in epigenetics. This suggests that there is much potential for transformation among diverse cell types.

The third state not only offers new insights into the adaptability of cells. It presents possibilities for new treatments. For example, anthrobots could be made from an individual’s living tissue to deliver drugs without triggering an unwanted immune response. Engineered anthrobots injected into the body could potentially dissolve arterial plaque in atherosclerosis patients and remove excess mucus in cystic fibrosis patients. Importantly, cells in these organisms have a finite life span. They die and are broken down after four to six weeks. This prevents the growth of potentially invasive cells. A better understanding of how some cells continue to function and metamorphose into multicellular entities some time after an organism’s demise holds promise for advancing personalized and preventive medicine.

More recently, researchers are contemplating the implications of taking cells from organisms that can be dead or alive—and turning them into cells with totally new functions. Namely, that this points to a biological third state — one that doesn't neatly fit into the categories of life and death. The third state challenges how scientists view cellular behavior. That is, biobots can develop new functions that make them unique. This is because there are few instances where organisms change in ways that are not predetermined. While other transformations, like caterpillars metamorphosing into butterflies, are part of a predetermined biological path. Cancer cells are also excluded, because they don't exhibit new functions, either.

But here's how the biobots are different.

Though the aforementioned anthrobots, for example, were taken from human lung cells, they were somehow able to repair damaged neuron cells placed nearby in a Petri dish, which they were able to move to on their own using writhing, hair-like projections called cilia. The anthrobots weren't engineered or programmed to do this. These properties emerged on their own. The xenobots also became mobile by using their cilia. This is novel, because in the frog cells they were derived from, the cilia are used to move mucus and not the cells themselves. The xenobots are also capable of self-replicating without growing, or repairing themselves. This shows that cells are inherently changeable and challenges the idea that cells and organisms can evolve only in predetermined ways. The third state suggests that organismal death may play a significant role in how life transforms over time.

A better understanding of how some cells continue to function and metamorphose into multicellular entities after an organism dies may help improve personalized and preventive medicine.