Despite the considerable advances in molecular biology over the past several decades, the nature of the physical–chemical process by which inanimate matter become transformed into simplest life remains elusive. In this review, we describe recent advances in a relatively new area of chemistry, systems chemistry, which attempts to uncover the physical–chemical principles underlying that remarkable transformation. A significant development has been the discovery that within the space of chemical potentiality there exists a largely unexplored kinetic domain which could be termed dynamic kinetic chemistry. Our analysis suggests that all biological systems and associated sub-systems belong to this distinct domain, thereby facilitating the placement of biological systems within a coherent physical/chemical framework. That discovery offers new insights into the origin of life process, as well as opening the door toward the preparation of active materials able to self-heal, adapt to environmental changes, even communicate, mimicking what transpires routinely in the biological world. The road to simplest proto-life appears to be opening up.
The recently developed field of synthetic biology is widely viewed as an engineering extension of biology involving ‘the synthesis of complex, biologically based (or inspired) systems which display functions that do not exist in nature' . However, if one takes a basic science approach to the topic, one could view the ultimate challenge of synthetic biology as the de novo synthesis of simple chemical systems exhibiting rudimentary biological characteristics. That kind of approach has barely been addressed in the past, and for good reason: the theoretical underpinnings for life-like chemical systems able to evolve from the chemical toward the biological have yet to be adequately clarified. Early pioneering ideas due to Oparin , Haldane  and Bernal  did open up the field to scientific discourse; however, quite awkwardly, a century after the modern synthesis set out to place the life phenomenon within a coherent mechanistic framework, life, as a physical–chemical phenomenon, remains poorly understood. Despite the dramatic advances in molecular biology over the past several decades, the conceptual gap separating the physical and biological worlds remains as wide as ever. As Kauffman recently put it : ‘despite the fine work . . . in the past three decades of molecular biology, the core of life itself remains shrouded from view. We know chunks of molecular machinery, metabolic pathways, means of membrane biosynthesis — we know many of the parts and many of the processes. But what makes a cell alive is still not clear to us. The center is still mysterious.' When the leading evolutionary biologist Carl Woese  was asked in 2012 just before his death to define life, he responded: ‘That's the problem. We can't.” In strictly physical–chemical terms, the nature of the life phenomenon remains elusive.
In this review, we wish to describe recent work in a newly emerging area of chemistry, systems chemistry, that attempts to break the conceptual logjam. In contrast with systems biology's top-down approach, systems chemistry takes a bottom-up approach in addressing the life phenomenon [7–10]. Through the study of molecular replicating systems on the one hand , and energy-fueled dynamic chemical processes maintained away from equilibrium on the other , it is now appearing possible to close in on the physical–chemical requirements that could allow a chemical system to begin to show rudimentary life-like characteristics. Some 160 years after Darwin initiated biology's integration within the physical sciences, the physical–chemical basis for the life phenomenon may be beginning to take shape. Biology may finally be connecting to its physical–chemical roots.
Seeking life's chemical roots
As noted, the life phenomenon has been a thorn in the side of physical–chemical theory for much of the last century. One long-standing difficulty is the fact that physical–chemical and biological systems appear to obey seemingly contradictory fundamental principles. While the direction of change in physical–chemical systems is governed by the thermodynamic directive [12,13], the behavior of biological systems seems strangely at odds with thermodynamic expectation. Though formally in agreements with that Second Law directive, living things maintain themselves away from equilibrium, and are directed toward complex, functional organization. What kind of chemical system could have initiated this strikingly different pattern of chemical behavior? Following recent advances in systems chemistry, we may now be closer to being able to answer that question. Our main message in this review article is that a new dimension in chemistry, a kinetic dimension, has been uncovered, one quite distinct to the well-established thermodynamic dimension which has dominated chemical theory and its practice for well over a century. For reasons which will be described, we have termed this new chemical dimension, dynamic kinetic chemistry , which contrasts with what one might call ‘regular’ chemistry, the kind normally associated with the traditional thermodynamic domain. We would go as far as to characterize this new area of chemistry as a new chemical dimension since it opens up new chemical potentialities that were unrealizable through traditional thermodynamic considerations. Lotka already understood the importance of kinetics a century ago when he stated that ‘thermodynamics only tells us what cannot happen, not what does happen’ . But the significance of this new chemical regime is that the living world may finally have found its physical–chemical home. Life turns out to be a complex manifestation of this newly discovered chemical dimension, so to understand life, at least in the first instance, is to understand the chemical basis for this kinetic dimension, and the likely attributes of chemical systems found within it. Let us now describe how such systems may be generated, and how an understanding of those systems may assist in the conceptual merging of the living and non-living worlds.
Dynamic kinetic chemistry
The interconversion of reactants X into products Y is governed primarily by thermodynamic considerations and can be simply represented by the symbolism: X ⇄ Y. Once the equilibrium state is reached, no further change in the equilibrium proportions of X and Y takes place. However, a steady-state mixture of X and Y, one that is maintained away from equilibrium, may be achieved through an energy-fueled transformation of X into Y, together with the dissipative transformation of Y back into X via an alternate reaction pathway [16–18]. The two interconversion kinds are depicted together in Figure 1. In the non-equilibrium case, the steady-state system of X and Y that is established, is governed by kinetic factors, not thermodynamic ones. However, the very existence of this kinetic domain opens up a new chemical dimension, one that is quite distinct to the traditional thermodynamic domain. The stability of systems within that domain has been termed dynamic kinetic stability (DKS) [19–27] to reflect the fact that the system is dynamic and the stability kind is kinetic, not thermodynamic (though quite distinct to static kinetic stability associated with entities trapped behind kinetic barriers). Importantly, for the DKS state to be maintained, a continuing source of energy needs to be supplied, and that energy supply is a central component of the DKS state description. Indeed, to appreciate the DKS concept, it is useful to think of the physical analogy of a water fountain, which expresses many of the characteristics of the DKS state — dynamic, non-equilibrium, energy-fueled, yet stable. The water fountain structure persists as long as energy is supplied to the pump that operates the fountain, enabling the physical non-equilibrium state to be maintained over time .
Schematic representation of the two general domains in chemistry, the traditional thermodynamic domain, and a newly characterized dynamic kinetic domain.
Dynamic kinetic energy-fueled interconversion of a carboxylate anion, RCOO− and its methyl ester, RCOOCH3, leading to a dynamic kinetically stable steady-state mixture of the two entities.
So why is this kinetic modification of the esterification reaction so significant? Its significance lies in the fact that entirely new physical properties can arise within such DKS systems. In the case of the van Esch, Eelkema system, the reaction mixture undergoes what has been termed dissipative self-assembly, leading to a gel-like structure whose character is very different from that observed following thermodynamic self-assembly [17,18]. Due to the system's dynamic character, the gel's properties are not static and predetermined, as one finds in thermodynamic self-assembly, but are dependent on the kinetics of the two-step process, and accordingly can be tuned for varying physical characteristics. In other words, kinetically controlled dissipative self-assembly opens up new horizons within material science, leading to materials with novel and variable characteristics. Specifically, it has recently led to the discovery of materials showing rudimentary biological character, such as the ability to undergo self-healing, to respond to environmental changes, even able to communicate in a limited sense . Though supramolecular systems under thermodynamic control can on occasion also show limited aspects of such a behavior, the extra degrees of freedom that open up within kinetic systems allow those characteristics to manifest more readily and in more striking ways [28–33].
Following the pioneering study of van Esch, Eelkema et al. a rash of kinetic systems displaying novel characteristics have appeared. For example, Hermans and colleagues  have described a perylene diimide derivative, which when maintained away from equilibrium by chemical fuels, undergoes a polymerization–depolymerization process, which displays oscillations, traveling fronts and macroscale self-organized patterns. Boekhoven and colleagues  have reported that an energy-fueled non-equilibrium mixture of carboxylic acids and their corresponding anhydrides leads to a self-selection mechanism for the more persistent anhydrides within liquid phase droplets. Klajn and colleagues  have described the generation of dynamically self-assembling ‘nanoflasks’ by light irradiation allowing the exploration of chemical reactivity in confined compartments. Prins and colleagues  were able to generate ATP-fueled dynamic, kinetically stable vesicles, whose life-times could be regulated, allowing particular chemical reactions to take place within those vesicles. Huck and colleagues  demonstrated the energy-fueled dissipative self-assembly of FtsZ protein into fibrils which then undergo division through their enclosure within coacervate compartments. Though the chemical detail associated with each of these examples varies widely, in all cases it is the dynamic, energy-fueled, kinetic character of those systems which leads to their unusual properties. The field of dynamic kinetic chemistry is in its infancy, with its potential only beginning to be uncovered.
Biology as dynamic kinetic chemistry
Whereas chemists may have stumbled upon the potential of dynamic kinetic chemistry relatively recently, nature has been exploiting that potential for literally millions, and in some cases, billions of years. Cytoskeleton dynamics, as well as muscle action, are based on just such energy-fueled, kinetically directed dynamic processes [34,35]. In the case of the cytoskeleton, it is the GTP-driven self-assembly of tubulin dimers to generate microtubules which leads to the cytoskeleton's structural characteristics and, in particular, to its dynamic and tunable character. That is how the cytoskeleton is able to partake in crucial cell functions, in particular active transport of material in and out of the cell, motility, as well as its central role during cell division. The cell's cytoskeleton is a prime example of a functional DKS system [34,35].
Proofreading, a central and critically important process in living systems, also turns out to be a dynamic kinetic phenomenon. As revealed by the pioneering contributions of Hopfield  and Ninio , proofreading mechanisms, such as those observed during DNA replication and ribosomal protein synthesis, are based on cyclic, non-equilibrium, ATP-driven kinetic processes.
But life's DKS character is even more fundamental. It can be found at the heart of all cell function. Proteins, the molecular entities central to all cell function, are typically stable molecules, yet cell protein half-life is surprisingly limited. In some instances, it can be as short as 10 min . Proteins exist in an energy-fueled dynamic kinetic state involving their continual turnover through the dynamic generation and degradation processes, and for good reason. A particular protein is likely to be required at a particular point in the cell cycle, so control over protein dynamics is crucial for proper cell function. Accordingly, intracellular protein also exists in a continual dynamic kinetic state .
The role of DKS in biology can be taken a step further. On further reflection, it becomes apparent that it is not just certain processes within the cell that should be thought of as exemplifying dynamic kinetic chemistry, but the cellular system as a whole. Ultimately the cell, in toto, is a dynamic, energy-fueled, non-equilibrium system, albeit a highly complex one. Homeostasis, which manifests the essence of the living state , is just the biological expression of what we can now identify as dynamic kinetic chemistry.
The conclusion is significant: biological systems may finally be characterizable in physical–chemical terms, and the entire biological world may be understood as a highly complex manifestation of that newly discovered kinetic dimension. Important implications derive from this insight. If the biological world is contained within this new chemical dimension, then the study of simple chemical systems which belong within that dimension will likely throw light on the physical basis of biology, as well as the physical–chemical means by which biology was able to emerge from inanimate beginnings. Biology's chemical essence may finally become explicable .
The nature of change within dynamic kinetic chemistry
Having defined a new chemical (kinetic) dimension, it now becomes necessary to delineate the principles that govern change within that kinetic dimension. In the ‘regular’ chemical world, the one dominated by thermodynamic considerations, it is the Second Law that is the operative directive [12,13]. However, in an energy-fueled kinetic world, thermodynamic considerations, though obviously relevant, only play a secondary role. Once an energy source is an intrinsic component of the system, Second Law constraints can be circumvented, much like a car with a supply of gasoline can overcome gravitational constraints and drive uphill. The question then arises whether there is a general rule of change for such energy-fueled systems, beyond its need to comply with entropic book-keeping. We believe the answer to be yes. Recently, such a general principle of change, one able to deal with both ‘regular’ chemical systems as well as energy-fueled systems, and therefore unshackled by thermodynamic constraints, was proposed — the Persistence Principle . The principle is a strictly logical one and can be stated as follows: nature is driven toward persistent forms. It follows directly from a tautology articulated by Grand: ‘things that persist persist, things that don't don't’ . The basis for the principle lies in the fact that the stability concept has two facets — time and energy — and stability's time facet, persistence, is more general than its energy facet . The relationship between stability's time and energy facets is revealed in the Venn diagram of Figure 2. Energy-stable entities (depicted by the shaded area) can be seen to be a sub-category of the broader time-stable category simply because energy-stable systems are invariably time-stable (persistent), but time-stable systems are not necessarily energy-stable. The conclusion that follows is striking: since time-stability is more general than energy-stability, it could indicate that a rule governing the direction of change based on time-stability will be more general than one based on energy-stability, i.e. the Persistence Principle is in some sense more general than the Second Law, even though the principle is necessarily bounded by Second Law requirements .
Categories of persistent systems: the more limited category of energy-stable entities as a sub-category within the more general category of time-stable systems.
So how will dynamic kinetically stable chemical systems, which are necessarily located within the time-stable region of the Venn diagram, change over time? According to the Persistence Principle, the change will be toward more persistent forms — from less persistent to more persistent. For open systems, however, when the system is open to energy and material exchange, precise prediction is not always possible as too many variables could be involved. But for a particular kind of DKS system, those that are replicative, the general direction of change can be predicted for reasons that are rooted in the mathematics of exponential growth, and turn out to express well-established evolutionary principles in biology . Thus central biological concepts, such as natural selection and fitness, are found to have their roots in more general physical–chemical principles.
Replicative DKS systems
In a landmark experiment carried out in the 1960s, Spiegelman observed an in vitro molecular evolutionary process for an extended RNA molecule subjected to multiple rounds of replication . That evolutionary process, however, was directed toward shorter, simpler RNAs, which replicated more rapidly, rather than toward more complex forms, toward life. More recently Kreysing et al.  demonstrated that under certain non-equilibrium conditions, DNA replication can be induced to form longer oligonucleotide chains; however, a generalized basis for complexification during evolution remains unclear. Consideration of replicative systems that have been excited into the DKS state [19–27] offers new insights into the issue of how complexity might arise during evolution. The math of exponential growth, often associated with replicating systems, predicts that when a replicating entity in the DKS state is able to undergo structural variation, then the more stable/persistent replicator will drive the less stable/persistent one into extinction [40,44,45]. In other words, a replicative system in the DKS state, which undergoes an evolutionary process, will be directed toward more stable DKS systems, rather than toward thermodynamically more stable systems. Importantly, however, when that expectation is coupled to the existence of a general relationship between replicative stability and complexity , then the reasons for an evolutionary process toward increasing complexity become clear. Bacterial cells, with their extraordinary structural and metabolic complexity, are remarkably robust, while replicating molecules are fragile and can only be induced to replicate under controlled laboratory conditions. It is the cell's exceptional complexity which brings about its exceptional stability/persistence.
A very recent experimental result from the Otto laboratory supports the prediction of increasing complexity associated with increasing replicative stability for competing macrocyclic DKS systems . When two replicating disulfide macrocycles, one trimeric in structure, the other hexameric, were induced into a DKS state (manifested by concomitant macrocycle generation and destruction and the establishment of an out-of-equilibrium, energy-fueled steady state) and allowed to compete for a common peptide thiol building block, the preferred product was the hexamer product, rather than the trimer product. The result was striking since the trimer macrocycle was found to be both kinetically and thermodynamically more stable than the hexamer product, yet the hexamer was not the preferred product. Furthermore, once the supply of chemical fuel was halted, resulting in the collapse of the DKS state, the reaction mixture reverted to being one in which the more stable trimer replicator became dominant. The bottom line is significant: once both trimeric and hexameric macrocycles were placed in the DKS state, the DKS more stable hexamer product predominated. That product, being larger and more complex, acted as a more effective catalyst for the replication reaction even though the rate constant for replication of the simpler trimeric macrocycle was greater than that for the larger, more complex system . Thus, as is normally observed during Darwinian evolution, the product manifesting improved replicative function, in this case the more complex one, turned out to be the preferred product.
From the above discussion, we learn that there appear to be two distinct global paths for material change, one toward increasing entropy, the other toward increasing (replicative) complexity, each leading to distinctly different material forms, as pictorially illustrated in Figure 3. Importantly, both paths derive directly from the mathematics of persistence. One path leads to persistence based on Boltzmann's probabilistic considerations (entropy), the other path derives from the mathematics of replication, Malthusian mathematics, leading to dynamic, time-stability/persistence. Though an evolutionary process toward persistence is observed along both pathways, the term ‘evolution’ is traditionally reserved for change along the energy-fueled replicative pathway .
Schematic diagram expressing the persistence principle and the two mathematical formulations through which stability/persistence may be expressed.
The above perspective leads to an insight that is contrary to traditional biological thinking. In tradition evolutionary thinking, the evolution process is considered directionless, the outcome of a blind algorithm . However, the above considerations suggest the reverse. Change in nature is always directed, both in the living and non-living worlds. In both worlds, change is directed toward more persistent forms, as logically it must. However, the mathematics of change in the two worlds are quite distinct, as depicted in Figure 3, thereby leading to the natural emergence of two material forms — living and non-living.
Feynman famously noted: what I cannot create, I do not understand. But that statement may be reversed with equal justification: what I do not understand, I cannot create. Systems chemistry's ultimate goal, what one might consider its Holy Grail, is the synthesis of a chemical system able to express key biological attributes, even if in just rudimentary form. Till recently that goal was out of reach. As stated earlier, without an understanding of what life is, how could one hope to create it. But with the discovery of a new dimension in chemistry, dynamic kinetic chemistry , new synthetic possibilities open up: what one does understand, one may be able to create. Life's essence, as well as many of life processes, lie within this new chemical dimension. Biological reality may have finally found its place within a general physical–chemical framework, something that was largely absent until now. Accordingly, the target of biology's synthetic goal can be stated more explicitly: to create a chemical system that is both replicative and in the DKS state, namely, non-equilibrium, energy-fueled, persistent to a degree, replicative and evolvable . The macrocyclic system recently reported by the Otto group , though limited in its evolutionary potential, appears to be the first experimental example of such a chemical system. Simplest synthetic proto-life now seems closer at hand.
The traditional approach toward the problem of life's emergence has been to speculate on likely prebiotic conditions that would have enabled that emergence. That approach, though informative in many respects, has not been able to resolve the fundamental question: how was it at all physically possible for living forms with their unique characteristics to have emerged? Historic elements were clearly involved; but, ultimately, the process is not fundamentally one of geography or the specification of particular prebiotic scenarios. A historic approach does not adequately address the ahistoric issue. In our view, the life challenge needs to focus more on identifying the driving forces able to operate in the physical–chemical world, forces responsible for inducing a change in the material world. Through the development of the DKS concept, we learn that the thermodynamic directive is not the sole driving force for chemical change in nature. Under appropriate conditions a kinetic driving force (toward greater DKS) can manifest itself with the result that quite distinct material forms can emerge, ones able to exhibit teleological character.
The implications are thought-provoking. Two millennia after Aristotle espoused the existence of a teleological world, and four hundred years after that teleological way of thinking was effectively banished by the modern scientific revolution, the possibility that there is a logical basis for teleology needs to be seriously reconsidered. Logical considerations now indicate that the world may be both objective and teleological, and that such paradoxical duality could well have a physical–chemical basis. The discovery of paradoxical duality within nature should not come as a complete surprise. Let us not forget the key discovery of 20th century physics, that matter's very essence rests on what would appear to be an inexplicable wave-particle duality. But just as that earlier realization changed our understanding of nature's laws in the most profound way, we believe that the realization that on the basis of mathematical/logical ideas, the cosmos could well be both objective and teleological, could prove to be highly significant. Paraphrasing de Duve , teleology may well be a cosmic imperative. The life phenomenon may well be an integral and understandable component of cosmic reality.
The recent discovery of a new domain in chemistry, dynamic kinetic chemistry, offers a conceptual bridge between the physical and biological worlds by providing a physical–chemical framework for biological systems and sub-systems.
The basis for the new kinetic domain lies in the existence of stable, dynamic, energy-fueled, far-from-equilibrium chemical systems expressing biological characteristics, such as the ability to self-heal and adapt to environmental changes.
The uncovering of a kinetic chemical domain offers new insights into the origin of life problem and offers a general recipe for the synthesis of simple proto-life. An early success toward achieving this goal is reported.
I thank Prof. Robert Pascal for extensive discussions during the course of writing this manuscript and Prof. Sijbren Otto for pertinent comments on an earlier version of this manuscript, as well as a preprint of ref. 48 prior to publication. Helpful comments from two referees and the Editor were also highly beneficial. Discussions and support from within the COST actions CM1304 Emergence and Evolution of Complex Chemical Systems and TD 1308 Origins, and the European Astrobiology Institute, are gratefully acknowledged.
The Author declares that there are no competing interests associated with this manuscript.