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Systems Chemistry: Steps Towards De-Novo Life

Periodic Reporting for period 3 - ToDL (Systems Chemistry: Steps Towards De-Novo Life)

Reporting period: 2020-09-01 to 2022-02-28

Can we synthesize life de-novo in the lab? This is one of the Grand Challenges of contemporary Science. Overall objective of this project is to set important steps in turning chemistry into biology by building fully synthetic chemical systems that contain and integrate some of the essential elements of life: replication, metabolism and compartmentalization. Ath the start of the project the functional coupling of any of life’s essential elements had not been achieved, at least not without making use of biomolecules. We now aim to achieve such coupling and develop fully chemical systems to become increasingly life-like. Specific aims are:
1. Achieve and explore Darwinian evolution of a fully synthetic system of peptide-based self-replicating molecules.
2. Develop self-replicating molecules that are capable of catalyzing not only their own formation, but also other chemical reactions. We will specifically target chemical reactions that result in the production of building blocks which the replicators can utilize to replicate, thereby integrating replication with a rudimentary form of metabolism.
3. Achieve self-reproducing compartments and develop ways to couple replication inside compartments with compartment division. Three parallel approaches will be explored, based on (i) vesicle-type compartments made from self-replicating molecules; (ii) coascervates and (iii) compartments made by surfactants that are produced by catalytically active self-replicators.
4. Extend replication from peptide-based building blocks to ones containing nucleobases. We also plan to investigate reaction networks made from mixtures of peptide- and nucleobase-containing building blocks.
5. Develop kinetic modelling tools that allow an efficient exploration of multi-parameter space of the reaction networks developed in 1-4. Through stochastic computational modelling we will address mechanistic issues that are experimentally intractable. Furthermore, modelling will allow a more efficient exploration of multi-parameter space and will guide further experimental work into the right part of this space.
With respect to the first aim (achieving Darwinian evolution): We have successfully developed a fully synthetic system of peptide-based self-replicating molecules which exhibits the key elements of Darwinian evolution: replication, mutation and selection. Depending on the environmental conditions a specific replicator wins the competition for a common resource.
Progress towards the second aim has also been good. A rudimentary form of metabolism has now been realized by self-replicators that are able to catalyze reactions of which the products accelerate the generation of the molecules that the replicators grow from.
Efforts towards compartmentalizing replicators have also been fruitful. In particular coascervates were found to be promising platforms for trapping replicators, while the molecules from which the replicators grow appear to be more free to diffuse between compartments.
Where the above results were obtained with peptide-based replicators, we recently also succeeded in making replicators containing nucleobases. Combining the two corresponding building block classes led to hybrid replicators featuring both peptides and nucleobases.
Finally, we succeeded in coding of a stochastic model that enables simulating replicating systems in unrivaled detail and are currently formulating and addressing key questions regarding replicator evolution with this model.
The most important new territory that was explored in the first half of the project involved developing metabolic replicators. Self-replicating molecular that can catalyze reactions other than their own replication represents a major breakthrough in the development of de-novo life, opening up new perspectives in the field. We expect to be able to develop catalytic activity further with the aim that replicators also catalyze the formation of compartments.
Path to de-novo life