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From self-replication to replicator systems en route to de novo life


The process by which chemistry can give rise to biology remains one of the biggest mysteries in contemporary science. The de novo synthesis and origin of life both require the functional integration of three key characteristics — replication, metabolism and compartmentalization — into a system that is maintained out of equilibrium and is capable of open-ended Darwinian evolution. This Review takes systems of self-replicating molecules as starting points and describes the steps necessary to integrate additional characteristics of life. We analyse how far experimental self-replicators have come in terms of Darwinian evolution. We also cover models of replicator communities that attempt to solve Eigen’s paradox, whereby accurate replication needs complex machinery yet obtaining such complex self-replicators through evolution requires accurate replication. Successful models rely on a collective metabolism and a way of (transient) compartmentalization, suggesting that the invention and integration of these two characteristics is driven by evolution. Despite our growing knowledge, there remain numerous key challenges that may be addressed by a combined theoretical and experimental approach.

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Fig. 1: Fundamental features of life and mechanisms of self-replication.
Fig. 2: Evolutionarily robust models of replicator communities.
Fig. 3: Completely synthetic self-replicating molecules.
Fig. 4: Self-replicating molecules featuring nucleic acids or peptides.
Fig. 5: Self-replication driven by supramolecular polymerization.
Fig. 6: Emergent catalysis in self-replicating systems.


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The authors thank A. Pross for discussions leading to the definition of dynamic kinetic stability. They are grateful for the EU Attract program (EmLife), the ERC (Advanced Grant ‘Towards de-novo life’; ToDL 741774), the Dutch Ministry of Education, Culture and Science (Gravitation program 024.001.035) and the National Research, Development and Innovation Office (NKFIH, Hungary) under grant numbers GINOP-2.3.2-15-2016-00057 and K119347, and the Volkswagen Stiftung initiative ‘Leben? — Ein neuer Blick der Naturwissenschaften auf die grundlegenden Prinzipien des Lebens’ under the project ‘A Unified Model of Recombination in Life’ for financial support. A. Szilágyi was supported by the Bolyai János Research Fellowship of the Hungarian Academy of Sciences.

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Systems chemistry

The study of properties that emerge from mixtures of interacting molecules. One of the key foci is the analysis and synthesis of diverse autocatalytic systems and their possible couplings.


Chemical processes that form the constituents of a living system from (often simple) raw materials (the food set) and connect the internal maintenance of the system to an external energy source.

Darwinian evolution

Evolution by natural selection that requires units that multiply and have heredity and variability. There should be hereditary traits that affect the chance of reproduction and/or survival of the units.


A system that enables spatial gradients (whereas chemists often consider bulk, well-stirred systems). Passive compartmentalization can be provided by absorptive surface and rock pores. Active compartmentalization rests on boundaries (such as membranes created through autopoiesis).

Out of equilibrium

Any state that is not at equilibrium.

Dynamic kinetic stability

A persistent state of an open chemical system resulting from a cyclic process of formation (replicative or otherwise) and destruction, occurring effectively irreversibly (that is, formation and destruction reactions are kinetically directed and not each other’s microscopic reverse), driven by continual material and/or energy input.


The ability of a system to autonomously catalyse the formation of copies of itself, such that information contained in the molecules that constitute the system is transferred to the next generation.

Exponential replication

An autocatalytic process with constant per-capita growth. Exponential replication leads to infinite concentration in infinite time. In competition, it entails survival of the fittest.


A complex process in which a system is able to produce more of itself and its constituent molecules.


The weighted distribution of mutants centred around one or several master sequences in a mutation–selection balance. The quasi-species is the target of selection in a system of replicating individuals who replicate without cooperating with one another.

Competitive exclusion principle

The principle that, in a replication–destruction regime harbouring self-replicators capable of exponential growth that compete for the same precursors (from which they replicate), one replicator will drive all others to extinction.

Eigen’s paradox

The paradox that accurate replication needs complex machinery, yet obtaining such complex self-replicators through evolution requires sufficiently accurate replication.

Open-ended evolution

A process whereby Darwinian replicator evolution proceeds indefinitely in a non-trivial manner. It may come in three forms: weak, strong and ultimate. In the weak form, novel phenotypes (not seen before, perhaps a new form of beak on a bird) arise indefinitely. The strong form requires evolutionary innovations, such as a novel catalytic or motor activity. The ultimate form allows for a major transition to occur, with the emergence of higher units of evolution from lower ones, such as reproducing protocells from replicating molecules.


The process in which one replicator consumes another (the prey) for its own replication. The predator population benefits, and the prey population suffers.


An ecological coupling between two populations from which both benefit. Analogous to a two-membered hypercycle.


A replicator set in which the autocatalytic replication of each member is heterocatalytically aided by another member conforming to cyclic topology.

Error threshold

The critical value of the mutation rate, above which errors accumulate and soon lead to the complete loss of information (error catastrophe) upon multiple rounds of replication. Stable selection requires that the error rate lies below the error threshold.


Replicators that take help from another without paying back. The helper pays a cost in terms of fitness by maintaining its helping capacity. Saving this cost, the parasite has a replicative advantage.


An RNA molecule that can act as a catalyst.

Collectively autocatalytic set

A reaction network in which no member is itself autocatalytic but the members catalyse the production or formation (but not the replication) of other members of the set. The set is collectively autocatalytic if the formation of every member is catalysed by at least one other member of the set.

Parabolic replication

Replication that is slower than exponential because the per-capita growth rate decreases with increasing replicator concentration.


The propensity of an informational molecule to join a collectively autocatalytic set rather than replicating itself directly.

Dynamic combinatorial library

A set of continuously interconverting oligomeric molecules made by linking building blocks together through a reversible reaction.

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Adamski, P., Eleveld, M., Sood, A. et al. From self-replication to replicator systems en route to de novo life. Nat Rev Chem 4, 386–403 (2020).

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