The Third State: Life Beyond Death

Life and death have conventionally been treated as opposites. Yet the appearance of new multicellular life-forms from the cells of a dead organism points to a "third state" outside the usual limits of life and death.

Scientists generally define death as the irreversible cessation of an organism’s overall functioning. Organ donation, however, shows that organs, tissues and cells may still operate after the organism itself has died.

That persistence prompts an important question: which mechanisms enable some cells to remain active after the death of an organism?

We study processes occurring inside organisms following death. In a review published recently, we outline how some cells, when supplied with nutrients, oxygen, bioelectricity or biochemical signals, can become multicellular organisms with new functions after death.

Life, death and the emergence of something new

The third state challenges the conventional scientific view of cell behaviour. Developmental changes such as a caterpillar becoming a butterfly or a tadpole developing into a frog are well known, but there are few examples of organisms changing in ways that have not been predetermined.

Tumours, organoids and cell lines capable of dividing indefinitely in a Petri dish, including HeLa cells, are not regarded as part of the third state because they do not acquire new functions.

Researchers have, however, shown that skin cells taken from dead frog embryos can adjust to the unfamiliar environment of a laboratory Petri dish and spontaneously rearrange themselves into multicellular organisms known as xenobots.

These organisms display behaviour that goes well beyond their initial biological function. Xenobots use cilia - tiny hair-like structures - to travel and navigate through their environment. In a living frog embryo, by contrast, cilia are normally used to move mucus.

Xenobots can also carry out kinematic self-replication: they can physically reproduce their structure and function without growing. This is unlike the more familiar forms of replication involving growth within, or on, an organism’s body.

Scientists have likewise discovered that individual human lung cells can assemble themselves into small multicellular organisms able to move about. These anthrobots have novel structures and behaviours. As well as navigating their environment, they can repair themselves and damaged neuron cells placed close to them.

Collectively, these results reveal the built-in plasticity of cellular systems and question the assumption that cells and organisms can develop only along predetermined pathways. The third state indicates that the death of an organism may have an important part in how life changes over time.

Postmortem conditions

Whether particular cells and tissues survive and function after an organism dies depends on several factors, including environmental conditions, metabolic activity and preservation methods.

Survival periods differ between cell types. In people, for instance, white blood cells die 60 to 86 hours after organismal death. In mice, skeletal muscle cells can be regrown 14 days after death, whereas fibroblast cells from sheep and goats can be cultured for around a month after death.

Metabolic activity is also crucial to a cell’s ability to remain alive and functional. Cells that need a constant, large energy supply to maintain their role are harder to culture than those with lower energy demands.

Preservation approaches, including cryopreservation, can enable tissue samples such as bone marrow to function in a similar way to samples from living donors.

Built-in survival mechanisms are another major influence on whether cells and tissues persist. Researchers have recorded a substantial postmortem rise in the activity of genes associated with stress and immunity, probably compensating for the loss of homeostasis.

In addition, trauma, infection and the length of time since death can considerably affect the viability of tissues and cells.

Age, health, sex and species type also influence the postmortem landscape. This can be seen in the difficulty of culturing and transplanting metabolically active islet cells - pancreatic cells that produce insulin - from donors to recipients.

Researchers think autoimmune processes, high energy demands and the breakdown of protective mechanisms may explain many failures of islet transplantation.

It is still unclear how these variables interact to allow certain cells to keep functioning after an organism has died. One possibility is that specialised channels and pumps in cells’ outer membranes act as complex electrical circuits.

By producing electrical signals, these channels and pumps allow cells to communicate and perform particular functions, including growth and movement, thereby shaping the organism they create.

It is also uncertain how extensively different cell types can transform after death. Earlier studies found that particular genes linked to stress, immunity and epigenetic regulation become active after death in mice, zebrafish and people, indicating that many different cell types may have the potential to transform.

Implications for biology and medicine

The third state provides fresh insight into cellular adaptability while also suggesting possibilities for new therapies.

Anthrobots, for example, could be created from a person’s living tissue to deliver medicines without causing an unwanted immune response. In theory, engineered anthrobots injected into the body could dissolve arterial plaque in patients with atherosclerosis and clear excess mucus in people with cystic fibrosis.

Crucially, these multicellular organisms have a limited lifespan and naturally break down after four to six weeks. This "kill switch" stops potentially invasive cells from growing.

Greater understanding of how certain cells can remain functional and metamorphose into multicellular entities after an organism’s death could help advance personalised and preventive medicine.

Peter A Noble, Adjunct Associate Professor of Microbiology, University of Alabama at Birmingham and Alex Pozhitkov, Senior Technical Lead of Bioinformatics, Irell & Manella Graduate School of Biological Sciences at City of Hope

This article is republished from The Conversation under a Creative Commons licence. Read the original article.