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Alive or life

In exploring the possible meeting surfaces between human action and the complexity of the living, our gaze can rest in an infinite number of places, from patterns on design objects to the search for life outside planet Earth. In the next articles, our gaze will rest on a particular category of technological constructs: biohybrid systems.

(The blood-brain barrier on a chip is shown above. The blue dye shows where the brain cells would go, and the red dye shows the pathway for blood circulation. )

Biohybrid systems blend biology and engineering to replicate the functions of living systems or to develop components with life-like behavior, improved biocompatibility, and better sustainability. They are designed and developed for industrial, clinical, and environmental purposes but also for basic research in robotics and biology.

In particular, by defining these systems as a category of their own, we propose a question that is not easy to solve: where is the boundary between artificial and biological components?

The hybrid nature of these entities embodies the encounter between two worlds that, when kept distinct, are able to define each other by the negation of the other, but when they meet highlight the incompleteness of definition of their relevance.

For example, I want to generalize, a biohybrid system is composed of an artificial and a natural part.

The artificial component of the system is directly opposed to the natural one, in this definition, and is said to be obtained with art. Where does human art stop and nature begin, in a biohybrid system? If humans are biological systems, are human art and technology, in fact, artificial? And is not a natural system employed lavishly to perform a technological function itself artificial?

These questions arise from the encounter between two worlds, which biohybrid systems bring about, and highlight the limited scope of the definitions present in our language. Wanting to name things, one strategy for constructing a coherent, appropriate, and complete definition of what makes up the biohybrid is to start by defining the isolated components.

The artificial component often has definitions "in the negative": everything that is not natural, the reproduction of something natural but made by man, the artifact. The theme of human design of the artificial product recurs, of the implementation of a project decided a priori, as opposed to the uncontrolled flow of nature.

Wanting to define what is natural, however, in the context of the study of biology we find ourselves wondering what the definition of a biological system is. This question points directly to a far-reaching question: what is life, and what is alive? Interestingly, this question has taken shape in the field of exobiology, a branch of biology that investigates the possibility of extraterrestrial life. In order to be able to recognize life outside of the environment in which we usually experience it, it must be defined.

In 2010, S. Benner explores this question with the article ​Defining Lifein the journal Astrobiology. The first point from which he starts is the clarification of the difference between the two definitions: "alive" and "life". Something that is alive may not have all the characteristics that are necessary to define life. For example, a cell in our skin is alive, but it is not life.

Benner cites one of the attempts to provide a universal definition of life, that of Koshland (2002): the seven pillars of life, or "PICERAS" definition, where PICERAS is an acronym for programming, improvisation, compartmentalization, energy, regeneration, adaptability, and seclusion.

Program An organized plan that describes both the ingredients themselves and the interactions among the ingredients so that the living system persists over time. In natural life as it is known on Earth, the program operates through the mechanisms of nucleic acids and amino acids, but the concept of the program can apply to other imagined or undiscovered mechanisms.

Improvisation The ability of a living system to modify its program in response to the larger environment in which it exists. For example, evolutionary processes and their impact on the genome of species.

Compartmentalization The separation of the spaces that make up a biological system that allows for the separation of environments in which different chemical processes take place. Compartmentalization is necessary to create a chemical environment that is protected from the outside world in which reactions can consume and produce chemicals in the right amounts.

Energy Since living systems necessarily move, and this corresponds to an increase in entropy, and an expenditure of energy, the latter is necessary for a living system to exist.

Regeneration The general compensation for losses and degradation of the various components and processes of the system: thermodynamic loss in chemical reactions, wear and tear of structural components, and decline due to aging. Living systems make up for these losses by importing molecules from the external environment, synthesizing new molecules and components, or giving rise to new generations of organisms.

Adaptability The ability of a living system to respond to needs, hazards, or changes. It is distinguished from improvisation because the response is timely and does not involve a change in the program. Adaptability occurs from a molecular level to a behavioral level through systems that react to events in the environment. For example, an animal that sees a predator might respond to danger with hormonal changes and escape behavior.


The separation of chemical pathways and the specificity of the effect of molecules means that processes can function separately within the same living system. In organisms on Earth, each protein has a precise structural conformation, which is specific to its function, so that it can act selectively on its targets without affecting other parts of the system.

These are the characteristics that define life according to Koshland. However, according to this definition, a rabbit considered individually would not be life, even if it has all the characteristics listed. Instead, a pair of rabbits capable of reproducing would result in life. Furthermore, the list captures the thermodynamic, genetic, physiological, metabolic, and cellular characteristics of terrestrial life as we know it. However, it offers no theoretical basis for arguing that these characteristics should be generalized to any life forms we have not yet observed.

Other definitions of life that attempt to offer such theoretical foundations have been proposed. For example, in 1994, Joyce summarized the discussion of a committee convened by NASA, at the suggestion of Carl Sagan, in these terms: ​life is a self-sustaining chemical system capable of Darwinian evolution.

The term "system" emphasizes the notion that entities can be alive (a cell, a virus, or a single rabbit) without themselves individually exemplifying life. The phrase "self-sufficient" is meant to imply that a living system does not require intervention by another entity to continue to be life. Darwin's theory of evolution draws together his observations that groups of organisms of the same species evolve gradually over time through the process of natural selection. In this context, the expression "Darwinian evolution" refers to the process, developed from this theory over the last 150 years. This is based on a molecular genetic system (DNA, in terrestrial life) that can be replicated, sometimes imperfectly. The errors resulting from imperfect replication can themselves be replicated, and the organisms that result from the variety of these replications are more or less well adapted to the environment. Depending on their degree of adaptation, the probability of passing genetic information to subsequent generations changes. And so, with generational cycles, the genetic makeup of each species also evolves, tracing its changes and adaptations to the environment.

In principle, current technology allows to artificially modify the genome of the offspring: our species in this way can override and modify Darwinian processes. How, then, does the reference to "Darwinian evolution" fit into Joyce's theoretical definition? Is it sufficient to include a novel mode of evolution: ​a self-sustaining chemical system capable of Darwinian or supra-Darwinian evolution​?

Questions about the relationship between what is natural and what is artificial, rather than resolving themselves, multiply.

In 2019, Vitas and Dobovisek publish the article ​Towards a General Definition of Lifeto modify and extend the 1994 NASA-proposed definition: ​life is a chemical system far from equilibrium that maintains itself, capable of processing, transforming, and accumulating information acquired from the environment.

What is new in this definition is the focus on the thermodynamic aspects of living systems. Thermodynamics is a branch of physics that deals with heat, work, and temperature, and their relationship to energy, radiation, and the physical properties of matter. Basically, the authors define life as a system far from equilibrium. When a system is in equilibrium, there is no flow of matter or energy, either within it or with the environment. In systems that are, by contrast, in a state far from equilibrium, there are fluxes of matter or energy. This definition of life thus holds in high regard the flow of information from the environment to the living system. The proposed new definition of life is independent of how genetic information evolves, and therefore includes both Darwinian and supra-Darwinian processes, being more easily extendable to other processes, now unknown, of information exchange between biological systems and the environment.

According to these definitions of what is alive and what is life, is a biohybrid system alive? Is it life? Where does one draw the line between life and artifice? Sometimes, one of the best ways to explore these questions is to construct the system under analysis. In future articles, several biohybrid systems will be recounted as we continue to explore the blurred and shifting boundary between what is and is not said to be life.

Roberta Bardini is a researcher in computational Biology and systems. She currently works at the Sysbio Group, Polytechnic of Turin, where she obtained her PhD. She deals with the development of multicellular organisms and their enhancement in the business environment.

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