Life/Citable Version

What is life? Biologists use the word 'life' for both the processes of living, and for the things that carry out those processes. Life, too, connotes the relationships among living things, past and present: it includes the entire living world — the biosphere — and the whole history of "life on earth". In theory, life might include entities, now unknown, that exist on other planets. Just what qualities would such beings have to possess for scientists to acknowledge them as alive? Could non-living things ever acquire those same qualities? What features separated the first living cells from the inanimate materials that formed them? The answers to such questions form part of the larger answer to that most basic of all questions in Biology: “what is life?" This article focuses not on 'life', the noun, but on 'living', the verb. What activities do living entities perform, and what processes enable them to perform them?

This article takes, as its theme, “Life is what is common to all living beings” (Christian De Duve) (see Biology and Systems biology).

Buzz of Life: One aspect of the interrelations among living entities. Researchers begin to understand the mechanisms governing the complex network interactions between plants and pollinators, such as hummingbirds, shown in this illustration from Ernst Haeckel's Kunstformen der Natur (1904).

Principles of life

Molecules

All known life is built from the same set of organic molecules: although they contain many elements, organic molecules always have a predominant structure of carbon linked to itself. In living things, organic species exist in mixtures of colloidal aqueous solutions that are never completely homogeneous, but are bounded by lipid and protein sheets. Each pool can have a different composition with distinct properties of charge, density, viscosity, and osmotic pressure, and it is these differences that provide the basis for the generation of electric fields, fluid shifts, and transport of molecules. The stuff of life, then, is carbon chains, studded with other atoms, and arranged in lagoons of fat, water, and salts, of differing compositions.

Cells

As well as sharing a common carbon- and water-based chemistry, every entity that biologists acknowledge as living — bacteria, trees, fish, chimpanzees — shares a common building block, the cell. Cells are universally enclosed in a membrane (a phospholipid bilayer known as the cytoplasmic membrane), that separates the inside of the cell from the external environment. Interestingly, the chemistry of the cell membrane is not universal. In many cells the molecules of the membrane are based on esters of glycerol combined with straight chain fatty acids, but in the Archaea the chemistry of membranes is based on glycerol ether linkages and isoprene fatty components.

Many organisms live as single cells, some as cooperative colonies of cells, and others as complex multicellular systems with many different cell types specialized for different functions. Nature has produced an enormous variety of cell types in three vast ‘domains’ of living systems: Archaea, Bacteria, and Eukarya, yet cells in all three domains have many features in common. All cells have a surrounding membrane; a physical boundary that separates them from their environment. The surface of that membrane always has special properties that allow protection, excretion, ingestion or communication. Often, these functions are provided by changes in the shape or actual chemical species present on the surface — so pores, receptor molecules and protective walls are often features of the cell surface. This is true in both unicellular and multicellular entities.

All cells are ‘manufactured’ by pre-existing cells, it is said. But then, how did the first cell begin?

That question can be approached indirectly, by looking at what all of the cells we know about have in common. All extract chemical energy from simple oxidation reactions, and convert it into other, chemical forms of energy. The molecule ATP is universally the cell's main energy 'currency'. All cells inherit stored information in the form of molecules of DNA, and they all use essentially the same universal genetic code to guide production of many different proteins, by tiny organelles called ribosomes. They use these various proteins to carry out diverse activities, including energy processing and conversion of carbon, nitrogen and phosphorous containing materials into cellular structures. In the human genome, about 22,000 different genes guide the production of hundreds of thousands of different proteins.

There is a huge diversity of single-celled organisms, but when we think of living things we think usually of large, complex animals or plants. These can contain vast numbers of cells, each part of a specialised subpopulation - in a mammal, the cells that make bone are very different from those that make muscle, and different again from those that make skin, for example. In a multicellular organism, cells combine to make organs, the functional and structural components of the single larger organism.

So what makes a single cell organism 'alive', and is this what we mean when we call a large complex multicellular animal 'alive'? What exactly do we mean by living?

Systems view of 'living'

(See main article, Systems biology)

Oocyte and spermatozoon merging to begin a new living system.

Ernst Mayr, a 20th century giant among evolutionary biologists, suggests that, to define 'life', we need to clarify what we mean by the process of 'living':

"The problem here is that 'life' suggests some 'thing' — a substance or force — and for centuries philosophers and biologists have tried to identify this 'vital force', to no avail. In reality, the noun 'life' is merely a reification of the process of living. It does not exist as an independent entity. One can deal with the process of living scientifically, something one cannot do with the abstraction 'life'. One can describe, and even try to define, what living is and what a living organism is, and one can try to make a demarcation between living and nonliving. Indeed, one can even try to explain how living as a process can be the product of molecules that themselves are not living."

The 'systems perspective' of living recalls Aristotle's four components of causality, , in that a living thing comprises:

• A list of organic and inorganic parts (molecules and ions; cells, organelles, organs and organisms) — Aristotle’s 'material' cause;
• How the parts relate to each other to form structures (e.g., networks), how they interact with each other (e.g., network dynamics), and how the structures interact with each other in a coordinated dynamic and hierarchical manner — Aristotle’s 'formal' (form-like) cause;
• How the parts and structures became organized (e.g., gene expression; self-organization; competition) — Aristotle’s 'efficient' (effect-producing) cause; and
• How the living system as-a-whole functions and behaves, and the properties that characterize it (e.g., reproduction; locomotion; cognition) — Aristotle’s 'final' cause

The analysis of all of those components together forms part of a new discipline, 'Systems Biology'. The phenomenon of 'emergence' is studied in that discipline; a phenomenom whereby properties, functions, and behaviors of living systems arise although they are not present in any individual component, and even when they are not predictable if all components are considered in isolation from the system. Every cellular system exhibits ‘emergent’ properties.

Why can't all of the properties of a system be predicted from the properties of its components? After all, the reductionist paradigm that dominated the Scientific method in the 20th century operated on the exact opposite assumption. There are two related reasons: first, the intrinsic properties of a system’s components do not determine those of the whole system; rather, their 'organizational dynamics' does, and those dynamics include not only the interrelations of the components themselves, but also interactions between those relationships. Second, the living system always operates in a context (its environment), and this, in turn, always affects the properties of the system-as-a-whole. The impact of context also affects the organization of the components within the system — a 'downward causation'.

Philosopher of science D.M. Walsh puts it this way: "The constituent parts and processes of a living thing are related to the organism as a whole by a kind of 'reciprocal causation'." In other words, the organization of the components determine the behavior of the system, but that organization arises from more than the set of its internal components. How the system behaves as it interacts with its environment determines how these components are organized, and so novel properties of the system 'emerge' that are neither in the environment or in that set of internal components. For example, the behavior of a human kidney cell depends not only on its cellular physiology, but also on all the properties of the organ (kidney) which constitutes its environment. The kidney's overall structure and function influence the cell’s structure and behavior (e.g., by physical confinement and by cell-to-cell signaling), which in turn influence how its intracellular components are organized. The kidney is similarly affected by its environment, which is the individual body that it lives in, and that body is affected by such factors as the availability of particular food items, fresh water, and ambient temperature and humidity. Systems biologists refer to those as 'bottom-up' and 'top-down' effects. The emergent properties that result from a combination of both bottom-up and top-down effects constitute general characteristics of living systems.

The thermodynamics of 'living'

Biologists often view living things from the perspective of thermodynamics — the science of interactions among energy (the capacity to do work), heat (thermal energy), work (movement through force), entropy (degree of disorder) and information (degree of order). The sum total of these interactions define what a system can and cannot do when interconverting energy and work. For example, by the First Law of Thermodynamics, when a process converts one form of energy to another, it results in no net loss of energy, and no net gain.

Scientists discovered the laws of thermodynamics through experiment, debate, mathematical formulation and refinement; Albert Einstein believed that they stood as an edifice of physical theory that could never topple. The Second Law of Thermodynamics may be most pertinent to an analysis of living systems:

Energy (electromagnetic: light and heat) emitted by our sun provides the great bulk of the energy gradient that living systems on earth exploit, either directly or indirectly, to maintain a state far from the equilibrium state of randomness. The photograph shows a handle-shaped cloud of plasma (hot ions) erupting from the Sun. Courtesy NASA/JPL-Caltech.[1]

• Heat flows spontaneously — i.e., without external help — from a region of higher temperature to one of lower temperature, and never spontaneously in the reverse direction. That also holds for other forms of energy, including electromagnetic and chemical energy — concentrations of energy disperse to lower energy levels, flowing “into the cool”, so to speak.
• When heat as input to a system causes it to perform work (e.g., in a steam engine), some heat always dissipates as ‘exhaust’, unused and unusable by the system for further work. That also holds for other forms of energy doing work; some of the energy always turns into ‘exhaust’, typically heat. Energy conversion to work in a system can never proceed at 100% efficiency.
• The degree of order or organization of a system and its surroundings cannot increase spontaneously. Scientists have learned how to put a number on the degree of disorder of a system, and they refer to it as entropy. Water vapor, with its molecules distributed nearly randomly, has a higher entropy than liquid water, with its molecules distributed less randomly, and a much higher entropy than ice, with its molecules distributed in a more organized crystal array. Left to itself, ice tends to spontaneously melt, and liquid water to evaporate. Order tends to disorder, with the Universe as a whole tending to exhaust itself into an ‘equilibrium’ state of randomness.

Those three expressions of the Second Law reflect the fact that energy and order spontaneously flow downhill — down a ‘gradient’ — toward eliminating the gradient, as if nature abhors gradients of energy and order. Upon gradient elimination, all energy and order has dissipated, all change ceases, and an equilibrium state ensues. Given this, how do living entities manage to come into existence, to develop from an ‘embryonic’ state to one of greater order and lesser entropy, and to perpetuate their order and increase in order? How do they thwart the Second Law?

They don’t: they only seem to do so. Actually, they exploit the Universe’s gradients of energy and order — which run 'downhill'. Like a steam engine, they ‘import’ energy and order, convert it, albeit incompletely, to the work of internal organization, and so reduce their internal entropy. But all along, they emit enough "exhaust" to increase the disorder and entropy of their surroundings, so that the total entropy of the living system and its surroundings increase, in keeping with the Second Law.

Biological cells qualify as non-equilibrium thermodynamic systems because they consume energy to live, and because they export unusable (degraded) energy to dissipate the energy gradient they find themselves in — in keeping with the Second Law. Living things can store energy and perform work both on themselves and their environment; only after a living thing dies do all parts relate to each other according to spontaneous physical and chemical processes. When alive, a living system always performs its organized functional activities far from the 'equilibrium' state of activity that would ensue if no energy could be imported: energy from outside supplies the driving force that keeps the system far from equilibrium. Non-equilibrium thermodynamic systems, including living things, can exhibit unexpectedly complex behaviors when maintained far-from-equilibrium, and one very remarkable behavior that can result from this disequilibrum is self-organization.

Moreover, some biophysicists propose that the production of order in an energy gradient, as occurs in living things, tends to develop inevitably and to proceed inexorably. They give two reasons for that: (1) the production of order, by exporting more than counterbalancing disorder, increases total entropy production (i.e., dissipates the energy gradient and renders the dissipated energy unusable) beyond that which would otherwise occur, and (2) energy sources dissipate their gradient to produce disorder at the fastest rate possible — to reach equilibrium as fast as it can. In other words, the physical principles governing energy gradient dissipation and energy degradation not only allows the development of living systems, but, in effect, tends to select for them, in particular, when no constraints are present disallowing their development (e.g., excess heat, poverty of appropriate chemicals). Thermodynamic principles thus may contribute not only to answering the question “what is life?” but also to “why is there life?”.

We can, then, view a living system as a state of organizational activity maintained by importing, storing and transforming energy and matter into the work and structures needed to sustain that state. They can only do so by producing waste and exporting it, and this lowers the organizational state of the environment. A living system maintains its organization at the expense of its external environment, leaving the environment more disorganized than the gain in organization of the living system — in keeping with the Second Law of thermodynamics. Thus, from a thermodynamic perspective:

A living system has the ability to remain for a time in a near steady-state as an organized system. The organization is made possible by the influx of energy and matter and by a more than compensatory efflux of waste (disorder), thereby allowing a far-from-equilibrium state to be maintained.

Evolutionary aspects of 'living'

Last Paragraph of Charles Darwin’s Origin of Species (1859) "It is interesting to contemplate an entangled bank, clothed with many plants of many kinds, with birds singing on the bushes, with various insects flitting about, and with worms crawling through the damp earth, and to reflect that these elaborately constructed forms, so different from each other, and dependent on each other in so complex a manner, have all been produced by laws acting around us. These laws, taken in the largest sense, being Growth with Reproduction; Inheritance which is almost implied by reproduction; Variability from the indirect and direct action of the external conditions of life, and from use and disuse; a Ratio of Increase so high as to lead to a Struggle for Life, and as a consequence to Natural Selection, entailing Divergence of Character and the Extinction of less-improved forms. Thus, from the war of nature, from famine and death, the most exalted object which we are capable of conceiving, namely, the production of the higher animals, directly follows. There is grandeur in this view of life, with its several powers, having been originally breathed into a few forms or into one; and that, whilst this planet has gone cycling on according to the fixed law of gravity, from so simple a beginning endless forms most beautiful and most wonderful have been, and are being, evolved." Full-Text Here

Historically, fires and storms have both achieved status as living entities in the imagination of mankind. Although some non-living entities, such as tornadoes or the flames of candles, exist, like living things, as non-equilibrium open thermodynamic systems, they lack essential qualities of living things, and those deficiencies remove scientific credence of the 'poetic' view. Tornadoes and candle flames cannot 'reproduce' themselves, as cells and organisms can. Fire may spread, tornadoes may split - but the full system that comprises each phenomenon does not self-replicate. Living systems not only have open access to the environment in terms of energy and entropy exchange, but also have the capability of reproducing themselves. When a living system reproduces itself, its offspring inherit its properties, but with variations introduced by random events (including 'mutations'). Some variations offer some of the offspring less opportunity to reproduce than others, and other offspring better opportunity, sometimes better even than their parents. Accordingly, new groups with different properties arise, that may supplant older groups because of their greater reproductive fitness. Biologists call this 'evolution by natural selection', and regard it as the most important way whereby living systems evolve over geological time..

Therefore, biologists recognize the ability to produce offspring that inherit some of its features, but with some variation due to chance, as an essential characteristic of living systems. They refer to it as descent with modification: Evolution by natural selection will occur if heritable variations produce offspring that differ in their reproductive fitness. The variations occur due to chance variations in the inherited genetic recipe (genotype) for constructing the organismic traits (phenotype). In all living systems, DNA primarily provides the genetic recipe. All living things extant today descended with modification from a single common ancestor, a unicellular organism.

Viruses have few of the characteristics of living systems described above, but they do have a genotype and phenotype, making them subject to natural selection and evolution. Accordingly, descent with modification is not uniquely a characteristic of living systems. Beyond the scope of this article, we find descent with modification in memes and the artificial life of computer software, such as self-modifying computer viruses and programs created through genetic programming. Descent with modification has also been proposed to account for the evolution of the universe.

Combining the thermodynamic and evolutionary perspectives, we might say that:

A living system has the ability to remain for a time in a near steady-state as an organized system. The organization is made possible by the influx of energy and matter and by a more than compensatory efflux of waste (disorder), thereby allowing a far-from-equilibrium state to be maintained. A system is also capable of participating in the transgenerational evolution of the species to which it belongs in adapting to changing environments.

The exobiologists' view

Exobiologists (also known as "astrobiologists") consider issues relating to the possible existence of extraterrestrial living systems. Dirk Schulze-Makuch and Louis Irwin attempted to distill the essential characteristics of a living system in their book Life in the Universe. They stress these characteristics, which resonate with the systems, thermodynamic and evolutionary perspectives discussed above:

• a microenvironment, with a boundary between it and its external environment,
• the ability of that microenvironment to transform energy and matter from the environment to maintain a highly ordered, 'organizational' state (a low entropy state),

• therefore, the ability of that microenvironment to remain in thermodynamic disequilibrium with its environment,

• the ability of that microenvironment to encode and transmit information.

Self-organization

Living systems organize themselves spontaneously. In cells, self-organization emerges in part from the chemical properties of the proteins that are encoded in their genes. Those proteins make their appearance through a genetic transcription-translation machinery, which represents a self-organized molecular machine that itself emerges, in part, from the chemical properties of proteins and other molecules. Molecules interact by forming and breaking strong covalent bonds, and also through weaker, quasi-stable non-covalent electromagnetic interactions, like hydrogen bonding and van der Waals' forces. Those interactions give aggregates of molecules the physical properties that underlie many biological processes.

One way to understand self-organization is to view the genetic information (the genome) as a 'computer program' that guides construction of the components of the cell that then arrange themselves according to their chemical properties. That arrangement, with the tinkering comprising local trial-and-error and evolution’s handiwork, can then carry out ('compute') integrative functions that are not explicitly encoded in the genome. The Nobel Prize-winning molecular biologist Sidney Brenner expressed the metaphor this way:

"...biological systems can be viewed as special computing devices. This view emerges from considerations of how information is stored in and retrieved from the genes. Genes can only specify the properties of the proteins they code for, and any integrative properties of the system must be 'computed' by their interactions. This provides a framework for analysis by simulation and sets practical bounds on what can be achieved by reductionist models.”

The patterns of structure and behavior in self-organized systems need no behind-the-scene 'master', and no prepared recipes that specify the structure and dynamics of the system. Instead, these patterns emerge from the interactions among the components of a system, dictated by their physical properties, and dynamically modified by the emerging organization, which is itself modified by the environment. Thus the single-celled zygote self-organizes into a multicellular living system as the genetically encoded proteins interact, responding to changing influences from the changing environment generated by growing multicellularity — becoming a network of many cell-types working cooperatively. Self-organized systems ultimately are products of a 'blind watchmaker'.

Self-organization tends to breed greater self-organization — and hence more complexity. Probably the most fundamental aspect of self-organization in cells lays in the tendency for lipids to form bilayers in an aqueous solution, and for non-polar moieties to congregate in non-polar envirionments, and for charged and polar moieties to congregate in polar solutions. Proteins can span both environments, or be selectively assigned to one or to the other according to their specific amino-acid sequence and side groups. Genes express not only proteins that organize themselves into a functional unit, but also proteins that organize themselves to regulate that unit, as in transcription regulatory circuits. Protein networks interact in a self-organizing way to produce networks of networks with complex levels of coordination. Cells communicate with other cells, either in free-living cellular communities or in multicellular organisms, and these communication activities self-organize by virtue of the properties of the cells, selected for fitness by evolutionary mechanisms, and responsive to downward regulation by environmental influences on the whole system.

Further elaborating the descriptions of living systems beyond the thermodynamic and evolutionary perspectives, we might say that:

A living system has the ability to remain for a time in a near steady-state as a self-organized system. The organization is enabled by the influx of energy and matter and by a more than compensatory efflux of waste (disorder), thereby exploiting a far-from-equilibrium state. A system is also capable of participating in the transgenerational evolution of the species to which it belongs in adapting to changing environments.

Autonomous agents

Views of a Foetus in the Womb (c. 1510 - 1512) is a drawing by Leonardo da Vinci. Detail. Although this near term fetus is a symbol of a new human life, the drawing is of a cadaver specimen. [2]

Stuart Kauffman uses the concept of 'autonomous agents' to explain living systems. He gives the hypothetical example of an enzyme that catalyzes the binding of two smaller sub-component molecules into a copy of itself — self-replication by 'auto-catalysis'. The energy to produce the enzyme comes from a neighboring molecule, by breaking an energy-rich bond, thus the neighbor molecule serves as a 'motor' to produce excess enzyme. The self-replication stops after using all duplicates of the motor, so to sustain self-replication, external energy — perhaps from light impinging on the system — must drive the repair of the broken chemical bond, re-establishing an ample supply of that energy-supplying molecule, thereby re-energizing the motor. A new cycle of 'auto-catalytic self-replication' can then begin, given an ample influx of both external energy and 'food' (sub-components of the 'auto-catalytic' enzyme). As an essential feature, interactions among the components of a system have effects (technically 'allosteric' effects) that help 'organize' and 'coordinate' its processes, allowing the self-replication to proceed.

Kauffman conceives, then, of an autocatalytic molecule in a network of molecules that has cycles of self-replication driven by external energy and materials. The network has a self-replication process as a subsystem, and a ‘motor’, namely, the breakup of an energy-rich molecule, supplying energy that 'drives' the self-replication, and its re-energizing repair by transduction of external energy. Kauffman calls such a network a 'molecular autonomous agent' because, given external energy (e.g. photons) and ample materials (the molecules needed to assemble the autocatalytic enzyme), the network perpetuates its existence;. The network is autonomous because it is not 'controlled' by outside forces even though it depends on outside energy and materials. The 'agent' is the system doing work autonomously; in this case, the work of auto-catalytic self-replication. (That's what 'agents' do; they do work.) In this example, the agent survives by ‘eating’ outside materials and energy. Work gets done because the system remains far-from-equilibrium: as energy flows through the system, the system does its work, and in so doing dissipates the energy gradient, but it temporarily constrains the rate of dissipation by storing energy in its internal organization. The agent continues 'to live' (survive and self-replicate) only while that far-from-equilibrium state exists, and it can be starved to 'death' by stopping the matter and energy from flowing through the system. Kauffman argues, from his example, that cells, and indeed all living systems, qualify as autonomous agents, constructed from molecular autonomous agents.

Autonomous agents also interest scientists in the fields of artificial intelligence and artificial life. One careful description of autonomous agents from some members of that group adds further insight to Kauffman's view of living systems:

"An autonomous agent is a system situated within and a part of an environment that senses that environment and acts on it, over time, in pursuit of its own agenda and so as to effect what it senses in the future. It has the properties of reactivity (timely response to environmental changes; autonomy (controls its own actions); goal-orientation (pursues its own agenda); continuous processing. Some autonomous agents may also have the properties of communicability (with other agents); adaptability (based on previous experience); unscripted flexibility."

For Kauffman, the property of pursuing its own agenda includes contributing to its own survival and reproduction: "...an autonomous agent is something that can both reproduce itself and do at least one thermodynamic work cycle. It turns out that this is true of all free-living cells, excepting weird special cases. They all do work cycles, just like the bacterium spinning its flagellum as it swims up the glucose gradient. The cells in your body are busy doing work cycles all the time." There is only one escape from work, and that is death.

If the descriptions of living systems from thermodynamic, evolutionary, self-organizational and autonomous agent perspectives are considered, we might say that:

A living system has the ability to remain for a time in a near steady-state as a self-organized system. It works autonomously to offset responses to perturbations, and to reproduce itself, enabled by the influx of energy and matter and by a more than compensatory efflux of waste (disorder), thereby exploiting a far-from-equilibrium state. Finally, it is capable of participating in the transgenerational evolution of the species to which it belongs in adapting to changing environments.

Networks

The modular organization of a cellular network. Yeast Transcriptional Regulatory Modules. Nodes represent modules, and boxes around the modules represent module groups. Directed edges represent regulatory relationship. The functional categories of the modules are color-coded. (Reproduced from Bar-Joseph Z et al. (2003) Computational discovery of gene modules and regulatory networks. Nat Biotechnol 21:1337–42) From: Qi Y, Ge H Modularity and dynamics of cellular networks. PLoS Comp Biol 2(12):e174

The science of networks provides another useful perspective on living things. Networks ‘re-present’ a system as a collection of ‘nodes’ and ‘interactions’ among the nodes (also referred to as ‘edges’ or ‘arrows’ or ‘links’). For example, in a spoken sentence, words and phrases make up the nodes, and the interconnections of syntax (subject-to-predicate, preposition-to-object of preposition, etc.) make up the links. Intracellular molecular networks represent specific functions in the cell; molecules make up the nodes, and their interactions with other nodes make up the edges or arrows. Some networks accept inputs of one kind and return outputs of a different kind.

One 'finds' networks everywhere in biology, from intracellular signalling pathways, to intraspecies networks, to ecosystems. Humans deliberately construct social networks, of individuals working (more or less) to a common purpose, such as the U.S. Congress; of electronic parts to produce, for example, mobile phones; of sentences and paragraphs to express messages, including this very article. Researchers view the World Wide Web as a network, and study its characteristics and dynamics.

According to Alon, "The cell can be viewed as an overlay of at least three types of networks, which describes protein-protein, protein-DNA, and protein-metabolite interactions." Alon notes that cellular networks are like many human engineered networks in that they show 'modularity', 'robustness', and 'motifs':

• Modules are 'subnetworks' that have a specific function, and which connect with other modules often only at one input node and one output node. Modularity facilitates adaptation to a changing environment, as, to produce an adaptation, evolution need tinker with a few modules rather than with the whole system. Evolution can sometimes 'exapt' existing modules for new functions that contribute to reproductive fitness. For example: the swim bladder, evolved as an adaptation for control of buoyancy, but was exapted as a respiratory organ in various groups of fish. .
• Robustness describes how a network is able to mainain its functionality despite environmental perturbations that affect the components. Robustness also restricts the range of network types that researchers have to consider, because only certain types of networks are robust.
• Network motifs offer economy of network design, as the same circuit can have many different uses in cellular regulation, as in the case of autoregulatory circuits and feedforward loops. Nature selects motifs in part for their ability to make networks robust, so systems use motifs that work well over and over again in many different networks. In several well-studied biological networks, the abundance of network motifs — small subnetworks — correlates with the degree of robustness. Networks, like those in cells and those in neural networks in the brain, use motifs as basic building blocks, like multicellular organisms use cells as basic building blocks. Motifs offer biologists a level of simplicity of biological functionality for their efforts to model the dynamics of organized hierarchies of networks.

The view of the cell as an overlay of mathematically-definable dynamic networks can reveal how a living system can exist as an improbable, intricate, self-orchestrated dance of molecules. It also suggests how the concept of self-organized networks can extend to all higher levels of living systems.

Further elaborating the descriptions of living systems beyond the thermodynamic, evolutionary, self-organizational and autonomous agent perspectives, we might say that:

A living system has the ability to remain for a time in a near steady-state as a self-organized system of hierarchical robust modular networks. It works autonomously to offset responses to perturbations, and to reproduce itself, enabled by the influx of energy and matter and by a more than compensatory efflux of waste (disorder), thereby exploiting a far-from-equilibrium state. Finally, it is capable of participating in the transgenerational evolution of the species to which it belongs in adapting to changing environments.

Information processing

Bioscientists study biological systems for many different reasons, hence biology has many subdisciplines (see Biology and List of biology topics). But in every subdiscipline, bioscientists study biological systems for the proximate reason of gaining information about the system to satisfy their however-motivated curiosity, and to apply that information to human agendas (e.g., to prevent disease, to conserve the environment). Those realities attest that biological systems harbor information, at least as people usually understand the term, 'information'. To appreciate how this perspective can contribute to understanding living systems, the following questions need answers:

• what do we mean by information?
• how does information apply to biological systems?
• how does information emerge in biological systems?
• how do the answers to those questions add to explaining living systems?

The word 'information' comes from the verb 'to inform', originally meaning to put form in something: the seal in-forms the wax, and the wax now contains in-formation. A random collection of particles or other entities has no form, nothing has given it form, and it contains no in-formation. The more randomness in the structure of the collection, the fewer improbable arrangements or interactions it has among its parts.

Information processing from DNA to a living system. Genes are made up of DNA, and contain the information used by other cellular components to create proteins. A cell is tightly packed with tens of thousands of proteins and other molecules, often working as multimolecular “machines” to perform essential cellular activities. Courtesy U.S. Department of Energy. http://DOEgenomestolife.org/pubs/overview.pdf or http://genomicsgtl.energy.gov/pubs/overview_screen.pdf

A drinking glass falls onto the sidewalk, it falls apart into a random collection of bits of glass. Notice it doesn’t regroup into the drinking glass — you could watch it for a lifetime. Our experience shows us that the drinking glass is more improbable than the glass in smithereens. The more improbable the arrangements, the more in-formation a collection of parts has received and therefore contains. An observer will conclude that something has happened to 'form' the parts into a more improbable state — an in-formation has occurred, and that the collection of parts contains that in-formation. By that reasoning, biological systems contain in-formation: something has happened to 'form' the parts into an improbable state.

An ordered desktop soon becomes disordered. The ordered desktop has message value, or 'information', in that something must have happened to give it form. The more unlikely the arrangement of the parts, the more information it contains. Biological systems have information content in that they are unlikely (non-random) arrangements of parts, non-random collections of interactions of parts, non-random collections of functional activities.

The thermodynamic and autonomous agent perspectives discussed cells as intermediates in a gradient of higher to lower forms of usable energy. The flow of energy through the cell feeds it, enabling it to work to gain form, or order, and to gain functionalities, raising its information content. The cell can do work on its environment also.

Thus a living system emerges as an information processing system. It can receive information from energy and materials in its environment, fueling and supplying the machinery that builds and sustains information-rich organization; it can generate new information inside itself, as in embryonic development; and it can transmit information within and outside itself, as in transcription regulation and exporting pheromones. From its parent, it inherits information that establishes its developmental potential and scripts its realization, — including information that enables it to reproduce itself.

Combined with other perspectives, viewing living systems as information banks, as inheritors, receivers, generators and transmitters of information, and as reproducers of inherited information, enables one to see living systems and their interactions with other living systems as a vast, complex, naturally-selected, self-sustaining, evolving communication network. Recently (on the timescale of evolving living systems) that evolving communication network emerged as the human brain, capable of communicating with itself and other humans using networks of 'symbols'. That led to the emergence of cultural evolution, a whole new domain of self-reproducing entities ('culturgens', 'memes') and descent with modification. That in turn led to the emergence of another vast communication network: books, wikis, and other technologies of information generation and exchange.

We might now consider another, closely related, perspective, a ‘cognitive’ perspective. Given that networks resist common perturbations (‘robustness’, ‘homeostasis’), one might think of them as containing a ‘representation’ of their environment and of how it might vary. As networks self-organize through interactions between proteins, any network ‘representation’ of its environment must derive from the genetic information that determines those proteins. The genetic information comprises a molecular code, and the process that transforms that information into proteins describes an algorithm — the transcription-translation algorithm. As these algorithms evolved through natural selection, one can view evolution as selecting for ‘cognitive’ functionality in the genome — the ability to ‘represent’ the cell’s environment, and more generally, to remember and anticipate.

Further elaborating beyond the thermodynamic, evolutionary, self-organizational, autonomous agent, and network perspectives, we might say that:

A living system has the informational content and information-processing faculty to remain for a time in a near steady-state as a self-organized system of hierarchical robust modular networks. It works autonomously to offset responses to perturbations, and to reproduce itself, enabled by the influx of energy and matter and by a more than compensatory efflux of waste (disorder), thereby exploiting a far-from-equilibrium state. Finally, it is capable of participating in the transgenerational evolution of the species to which it belongs in adapting to changing environments.

Life involves organic chemistry

Why the central place of carbon in the chemistry of all earth’s living things? The physical chemistry of carbon allows it to bond with many other elements, especially hydrogen, oxygen, nitrogen and phosphorus, and, even to form carbon-to-carbon bonds. The avidity for carbon to bond to itself allows carbon atoms to easily join into long chains and closed rings; and allows small organic molecules (such as sugars, amino acids and nucleotides) to join into huge macromolecules that are remarkably stable at standard conditions.

The variety of carbon bonds vary in strength as well as in 3-D conformation; adding a dynamic quality to many organic molecules. The simplest set of bonds that carbon can form is that of a tetrahedron, or pyramid. Other types of bonds involve more than one shared electron, and for that reason are called double, and triple bonds; importantly, these different bonds constitute three entirely different geometries. Changing from one type of carbon-to-carbon bond to another type, as when a double bond is reduced to a single bond, will cause energy changes but without destroying the molecule. Such changes not only affect free energy, but also affect the actual shape of the molecule and the particular side groups attached to it. In this way, for at least some organic molecules, the 'pulse of life' is represented at an atomic level.

These properties of carbon mean that organic macromolecules are capable of containing tremendous 'banks' of information coded in their very structure. Not only can each of the constituent molecules be huge, but several categories of chemicals, like nucleotides or amino acids, that contain several different species, can be ordered so that the possible combinations are effectively limitless. All of these molecules are involved in the molecular-interaction networks of cells. Amogst these networks of interactions are those that enable cells to import and transform energy and energy-rich matter from the environment and that ultimately enable cells to grow, survive and reproduce.

Elsewhere in the universe, where conditions differ greatly from earth’s, other atoms may hold a central place in life. Silicon, carbon's close relative on the periodic table, also forms bonds with itself, but they readily disassociate at the temperatures that are compatible with life as we know it. That is not true at much higher temperatures, and so it is possible to imagine biochemical reactions, more or less as we know them, occurring at, say, 400 degrees Celsius with silicon taking the place of carbon. If they do, one would expect that they too could form structures of such variation in size, shape, charge and composition that might be used to contain and organise information.

Identifying the different scientific perspectives on life

Signs of life. Top: Spermatozoon and oocyte merge to begin a new building block for a living system. Middle: DNA, the recipe of life. (Courtesy Department of Energy Gallery) Bottom: life encoded in books.

The different perspectives biologists use in viewing living systems can be identified as follows:

• Living systems import energy, matter, and information from their environment, and export waste. This flow enables living systems to organize and maintain themselves, and thus to delay (for their lifetime) the dictate of the Second Law of Thermodynamics, that organized systems ultimately degrade to a state of randomness;
• The basic building blocks of all living systems are cells; the basic (genetic) information that generates cells comes as part of their starting materials. This information, in the form of nucleic acid macromolecules, encodes many different types of proteins that interact to assemble an organization that can import energy and export waste. Cells inherit this information from ‘parent’ cells, raising two as yet unanswered questions: how did cells arise in the first place? and how did they acquire stores of information?; (see Origin of life and Evolution of cells)
• The molecular interactions are governed by the universal laws of physics and chemistry; those laws, together with the inherited information, enable a self-organizing system that can work autonomously for survival and reproduction, and allow properties to emerge that could not be anticipated from those of the system's components alone.
• The activities of a living system occur without a 'master controller'; they need only a type of organization that maintains the system far-from-equilibrium, which can yield improbable self-organized structures and activities.
• Living things cannot escape from changing external conditions, so they must exhibit robustness in their organization and must be adaptable to maintain their stability. Robustness and adaptability derive from the properties of a hierarchical network of subnetworks of molecular circuits;
• Living systems must produce enough reproductive variability to allow evolution through natural selection, which guides the continuation of a 3.5 billion year history of Earth’s ‘living’ world. By evolution, living systems generate increasing varieties of living systems, occupy an extreme spectrum of environments, create their own environments, and permit sufficient complexity to enable them to process information in a way that allows them to ‘experience’ themselves.

Synthesis of perspectives on what constitutes Life

The activity of living, for a cell-based system, depends on the ability to maintain a near steady-state of organized functioning far from the state of randomness. The system achieves that in part because of its location in the path of a downhill gradient of flowing energy. It exploits that gradient through its abilities to import some of the energy flowing past it, and to export unusable energy and material, thus increasing its own order at the expense of a more than counterbalancing disorder of its surroundings.

Those principles seem to apply to all living systems: single cells, multicellular organs and organisms, and multi-organism demes and ecosystems.

The building block of all living systems is the cell. For cells to utilize available external energy, or energy-rich matter, and achieve order, they must have, from the outset, some informational content. That enables the cell to produce components that can, through molecular interactions, respond to the imported energy and material to organize themselves. That organization comprises modular networks of molecular interactions, and networks of interacting networks — self-organized and coordinated functional interactions. The properties of the networks and those of the hierarchy of networks enable the system to perpetuate itself, and allow it to maintain its steady-state despite fluctuations in environmental factors. That principle, too, applies to all living systems. An organism, plant or animal, comprises a network of organs working autonomously, maintaining its steady-state functioning far from equilibrium in response to environmental perturbations — physiologists refer to that as homeostasis.

The networks that regulate the flow of information through the cell were 'designed' by natural selection and other evolutionary processes. That is, evolution selected the codes for the molecules that had the properties that enabled them to interact in ways that contribute to self-organization of just those networks whose dynamic overlay creates a functioning cell capable of sustaining and reproducing itself. The collaboration of natural selection and physico-chemical laws serves to perpetuate living systems not only in real-time but also in geological, or ‘evolutionary’, time. From one common ancestor cell — however that may have arisen — informationally-guided, self-organizing, autonomous network dynamics enabled generation of the diversity of all living systems on the planet, over a period of more than three billion years. Living systems perpetuate living systems, exploiting free energy on its inexorable path to dissipation and degradation, harvesting energy in developing systems organization by a more than counterbalancing dis-organizing of the larger system in which it is embedded.

Further reading

Books

• Schrodinger E (1944-2000) "What is Life?" Cambridge University Press (Canto). ISBN 0-521-42708-8 Chapter 6: Order, Disorder and Entropy (Prediction of hereditary molecule like a coded periodic crystal — Watson claims inspiration — Stresses open thermodynamic systems key to life.)
• Kaneko K (2006) "Life: An Introduction to Complex Systems Biology." Springer, Berlin ISBN 3-540-32666-9
• Dill KA, Bromberg S, Stigter D (2003) "Molecular Driving Forces: Statistical Thermodynamics in Chemistry and Biology." Garland Science, New York. ISBN 0-8153-2051-5
• Strogatz SH (2003) "Sync: The Emerging Science of Spontaneous Order." Theia, New York ISBN 0-7868-6844-9
• Buchanan M (2002) "Nexus: Small Worlds and the Groundbreaking Science of Networks." W.W. Norton, New York ISBN 0-393-04153-0
• Hoagland M, Dodson B, Hauck J (2001) "Exploring the Way Life Works: The Science of Biology." Jones and Bartlett Publishers, Inc, Mississauga, Ontario ISBN 0-7637-1688-X (Wonderful especially for young people. An illustrated text.)
• Solé R, Goodwin B (2000) "Signs of Life: How Complexity Pervades Biology." Basic Books, Perseus Books Group, New York ISBN 0-465-01928-5
• Loewenstein WR (2000) "The Touchstone of life: Molecular Information, Cell Communication, and the Foundations of Life." Oxford University Press ISBN 0-19-514057-5 Book Review and Chapter One
• Hoagland M, Dodson B (1998) "The Way Life Works: The Science Lovers Illustrated Guide to How Life Grows, Develops, Reproduces, and Gets Along." Three Rivers Press, New York ISBN 0-8129-2888-1 (Wonderful especially for young people. An illustrated text.)
• Margulis L, Sagan D (1995) "What is Life?" Simon & Schuster ISBN 0-684-81087-5

Articles

• Epstein IR, Pojman JA, Steinbock O. (2006) Introduction: Self-organization in nonequilibrium chemical systems. Chaos 16:037101 PMID 17014235
• Hazen R. (2006) The Big Questions: What is Life? New Scientist Issue 2578, 46-51
• Marenduzzo D et al. (2006) Entropy-driven genome organization. Biophys J 90:3712-3721 PMID 16500976
• Morowitz H, Smith E (2006) Energy flow and the organization of life
• Scheffer M, van Nes EH (2006) Self-organized similarity, the evolutionary emergence of groups of similar species. Proc Natl Acad Sci USA 103:6230-6235 PMID 16585519
• Walsh DM (2006) Organisms as natural purposes: The contemporary evolutionary perspective. Studies in History and Philosophy of Science. Part C: Studies in History and Philosophy of Biological and Biomedical Sciences 37:771-791 Link to Article
• Park K, Lai YC, Ye N (2005) Self-organized scale-free networks. Phys Rev E Stat Nonlin Soft Matter Phys 72:026131 PMID 16196668
• Troisi A, Wong V, Ratner MA (2005) An agent-based approach for modeling molecular self-organization. Proc Natl Acad Sci USA 102:255-260 PMID 15625108
• Pace NR. (2001) Special Feature: The universal nature of biochemistry. Proc Natl Acad Sci USA 98:805-8
  
• Dronamraju KR. (1999) Erwin Schrodinger and the origins of molecular biology. Genetics 153:1071-1076 PMID 10545442 Link to Journal

Interviews and Commentaries

• Kauffman S. The Adjacent Possible: A Talk with Stuart Kauffman

See also in Citizendium

• Origin of life
• Evolution
• Evolution of cells
• Biology
• Systems biology
• Metabolism

External links not cited above

• "In the Beginning..." (The Economist)

• From the preface: "How life on Earth got going is still mysterious, but not for want of ideas."

• Stanford Encyclopedia of Philosophy entry

• Excerpt from Conclusion: "“Living organisms are autopoietic systems: self-constructing, self-maintaining, energy-transducing autocatalytic entities” in which information needed to construct the next generation of organisms is stabilized in nucleic acids that replicate within the context of whole cells and work with other developmental resources during the life-cycles of organisms, but they are also “systems capable of evolving by variation and natural selection: self-reproducing entities, whose forms and functions are adapted to their environment and reflect the composition and history of an ecosystem” (Harold 2001, 232)."

• Life under extreme conditions.

Appendix A

Other characteristics shared by all living things

Living things share some very specific features not always explicitly stated above. For example,

• in addition to the principle of parsimony, much evidence supports the proposition that all extant living things descended from a common ancestor
• only pre-existing cells can "manufacture" new cells;
• only pre-existing multicellular organisms can 'manufacture" new multicellular organisms;
• a membrane encloses every cell, protecting each from dissolution into its external environment;

• the cell membrane contains molecular systems that enables the cell to import usable matter and energy and to export unusable matter and energy, and others that enable it to send and receive signals to and from other cells;

• all cells and multicellular systems eventually die.

Appendix B

Selected definitions of life

Marcello Bárbieri, Professor of Morphology and Embryology at the University of Ferrara, Italy, collected an extensive list of definitions of “Life” from scientists and philosophers of the 19th and 20th centuries. Those selected below resonate with the systems and thermodynamic perspectives of living systems:

• "The broadest and most complete definition of life will be "the continuous adjustment of internal to external relations". — Hebert Spencer (1884)
• "It is the particular manner of composition of the materials and processes, their spatial and temporal organisation which constitute what we call life." — A. Putter (1923)
• "A living organism is a system organised in a hierarchic order of many different parts, in which a great number of processes are so disposed that by means of their mutual relations, within wide limits with constant change of the materials and energies constituting the system, and also in spite of disturbances conditioned by external influences, the system ts generated or remains in the state characteristic of it, or these processes lead to the production of similar systems." — Ludwig von Bertalanffy (1933)
• "Life seems to be an orderly and lawful behaviour of matter, not based exclusively on its tendency to go from order to disorder, but based partly on existing order that is kept up." — Erwin Schrodinger (1944)
• "Life is made of three basic elements: matter, energy and information. Any element in life that is not matter and energy can be reduced to information." — P.Fong (1973)
• "A living system is an open system that is self-replicating, self-regulating, and feeds on energy from the environment." — R. Sattler (1986)

Published collections of definitions of 'Life'

• Popa R (2004) Chronology of Definitions and Interpretations of Life. In: Popa R, ed. Between Necessity and Probability: Searching for the Definition and Origin of Life. Berlin: Springer-Verlag 2004: pp. 197-205

• Quotes and source-citations from 1885 to 2002 CE

• Barbieri M (2003) Appendix: Definitions of Life. In: The Organic Codes: An Introduction to Semantic Biology. Cambridge, UK: Cambridge University Press ISBN 0521824141

• Quotes from 1802 to 2002

The gray zone

Not all entities that otherwise qualify as living reproduce themselves, although they exist as reproduced living things. Biologists call such living things 'sterile'. Examples include programmed sterility (e.g., worker ants, mules); acquired sterility (due to acquired injury (disease) to the reproductive process; access sterility (lack of reproductive fitness); voluntary sterility (e.g., human couples). Obviously living things with the capacity to reproduce may die before reaching the reproductive stage in their life-cycle. Conversely, non-reproducing individuals may still effect reproduction of copies of their genes by facilitating the reproduction of kin, who share many genes (see kin selection).

Viruses would not qualify strictly as living things, but manage to 'reproduce' in living systems.

One might ask whether a spermatozoon qualifies as a living entity. From the thermodynamic perspective, one might answer affirmatively, as it keeps itself ‘living’ by doing cellular work. It has a compartmentalized internal organization functioning to keep it far-from-equilibrium. In that respect it resembles a motile bacterium. A spermatozoon reproduces, but in a different way than a motile bacterium: it does it through its parent’s progeny, which the spermatozoon plays an essential role in generating. It doesn’t have to hijack a cell’s machinery to reproduce; it cooperates with another cell (an ovum) to generate cells with machinery to reproduce it. Moreover, in reproducing that way, it subjects itself to meiotic crossover variation, just as its parent’s progeny does, contributing to the variation needed by natural selection to perpetuate the process of living on an earth with ever-changing environments.