Bottom up Synthesis of Complex Biological Model Systems
Lead Research Organisation:
University of Oxford
Abstract
In the pursuit to address questions such as 'In what form did life originate?' and 'What are the requirements for complex life-like behaviour?' the Fletcher group has developed chemical systems capable of self-replication. This allows the exploration of whether a minimal system can mimic the patterns and behaviours we see in life and which specific design features give rise to which phenomena. Just like the power of DNA replication seen in organisms today there is some widespread agreement that self-replication concepts could have been key to unlocking complexity and evolution in prebiotic scenarios.1,2 For this reason a number of groups interested in prebiotic chemistry have developed novel chemical systems able to compartmentalise and grow, each with the concept of self-replication at their core.3,4
Our current approach relies upon the phase separation of the reactants to provide a degree of order, much like the localisation of metabolic activities within a cell. Reactions that occur across an interface can be subject to positive feedback mechanisms provided the reaction alters some property of the interface, such as surface area. In our case, this effect is achieved using a thiol-disulfide exchange reaction established by Morrow and coworkers.6 This involves the interaction of hydrophobic (1) and hydrophilic (2) reaction partners as depicted in Figure 1 to transiently form an unstable micellar surfactant product 4 whose population is sustained by the addition of a chemical oxidant. This work embodied a core feature of life-like systems in that they exist in a kinetically stabilised state, constantly requiring fuel to avoid decay.7 More recent work has focused on developing closely related replicators with differences in their formation rates, stabilities and ability to oxidise. This has allowed the observation of competition and parasitic-like behaviour between different species and the recycling of aromatic thiol 3 by aerobic oxidation to sustain a fuelled system.
Using an alternative chemical replicator, coworkers within the group have also coupled the movement of oil droplets to the production of a surfactant.8 As the reaction proceeds, a surface tension gradient is established on the droplet resulting in the flow of propellant over its surface and the generation of internal convection currents (see Figure 2). This work demonstrated further properties of life-like entities, namely the partitioning of protocell droplets and fuelled directional movement.
Project aims and impact:
Future investigations will aim to understand the reasons for complex behaviour in the thiol-disulfide system by obtaining richer data and determine the key parameters and physicochemical steps (e.g. phase transfer) that give rise to the observed patterns. Building upon the prior work summarised above, we also aim to use the internal convection currents created within oil droplets to drive further chemical work. By the implantation of appropriate reagents within the oil droplet we envisage that the convection currents could promote a secondary chemical reaction thereby mimicking a simple metabolic sequence such as could conceivably be found involving a rudimentary organelle. One possible extension on these themes could aim to link phase separated processes, ultimately generating a pool of relatively complex self-replicators that were successful in navigating a route from simple building blocks. Achievement of this goal would be a direct analogy to the selection and mutation behaviour seen in biological evolution.
This project falls within the EPSRC Physical Sciences themes of Synthetic Organic Chemistry and Chemical Reaction Dynamics and Mechanism however its outcomes may ultimately also have implications in the fields of Synthetic Supramolecular Chemistry and Synthetic Biology.
Our current approach relies upon the phase separation of the reactants to provide a degree of order, much like the localisation of metabolic activities within a cell. Reactions that occur across an interface can be subject to positive feedback mechanisms provided the reaction alters some property of the interface, such as surface area. In our case, this effect is achieved using a thiol-disulfide exchange reaction established by Morrow and coworkers.6 This involves the interaction of hydrophobic (1) and hydrophilic (2) reaction partners as depicted in Figure 1 to transiently form an unstable micellar surfactant product 4 whose population is sustained by the addition of a chemical oxidant. This work embodied a core feature of life-like systems in that they exist in a kinetically stabilised state, constantly requiring fuel to avoid decay.7 More recent work has focused on developing closely related replicators with differences in their formation rates, stabilities and ability to oxidise. This has allowed the observation of competition and parasitic-like behaviour between different species and the recycling of aromatic thiol 3 by aerobic oxidation to sustain a fuelled system.
Using an alternative chemical replicator, coworkers within the group have also coupled the movement of oil droplets to the production of a surfactant.8 As the reaction proceeds, a surface tension gradient is established on the droplet resulting in the flow of propellant over its surface and the generation of internal convection currents (see Figure 2). This work demonstrated further properties of life-like entities, namely the partitioning of protocell droplets and fuelled directional movement.
Project aims and impact:
Future investigations will aim to understand the reasons for complex behaviour in the thiol-disulfide system by obtaining richer data and determine the key parameters and physicochemical steps (e.g. phase transfer) that give rise to the observed patterns. Building upon the prior work summarised above, we also aim to use the internal convection currents created within oil droplets to drive further chemical work. By the implantation of appropriate reagents within the oil droplet we envisage that the convection currents could promote a secondary chemical reaction thereby mimicking a simple metabolic sequence such as could conceivably be found involving a rudimentary organelle. One possible extension on these themes could aim to link phase separated processes, ultimately generating a pool of relatively complex self-replicators that were successful in navigating a route from simple building blocks. Achievement of this goal would be a direct analogy to the selection and mutation behaviour seen in biological evolution.
This project falls within the EPSRC Physical Sciences themes of Synthetic Organic Chemistry and Chemical Reaction Dynamics and Mechanism however its outcomes may ultimately also have implications in the fields of Synthetic Supramolecular Chemistry and Synthetic Biology.
Planned Impact
This programme is focused on a new cohort-driven approach to the training of next-generation doctoral scientists in the practice of novel and efficient chemical synthesis coupled with an in-depth appreciation of its application to biology and medicine.
This collaborative academic-industrial SBM CDT will have long-term benefit to the chemical industry, including the pharmaceutical, agrochemical and fine chemical sectors. These industries will benefit through: (i) the potential to employ individuals trained with broad and relevant scientific and transferable skills; (ii) new approaches to the investigation of complex biological and medical problems through novel chemistry; and (iii) better and more efficient synthetic methods.
We will link the work of DSTL, and our pharmaceutical and agrochemical partners (GSK, UCB, Vertex, Evotec, Eisai, AstraZeneca, Syngenta, Novartis, Takeda, Sumitomo and Pfizer) through a common theme of synthesis training. The design and synthesis of new compounds is essential for disease treatment and prevention, and for maintaining food security. Synthesis contributes significantly to UK tax revenue and results in sustained employment across a number of sectors. Employers in the finance, law, health, academic, analytical, government, and teaching professions, for example, also recognise the value of the translational skill-sets possessed by synthesis postgraduates, which this programme will provide.
The SBM CDT training programme will adopt an IP-free model to enable completely free exchange of information, know-how and specific expertise between students and supervisors on different projects and across different industrial companies. This will lead to better knowledge creation through unfettered access to information from all academics, partners and students involved in the project. By focussing on basic science, we will engender genuine collaboration leading to enabling technology that will be of use across a wide range of industries.
We will train the next generation of multidisciplinary synthetic chemists with an appreciation of the impact of synthesis in biology and medicine. Their unconstrained view of synthesis will aid in new scientific discoveries leading to new products, which (with appropriate inward investment), can lead to the formation of new companies and new UK employment.
We will, in part through an alliance with the Defence, Science and Technology Laboratory, engage with policy-makers to influence future policy issues involving chemistry such as food security and the rise of antibiotic resistance (both of which are relevant to our programme and are important for society as a whole).
Outreach and public engagement will be a key aspect of our programme; and all students in the proposed SBM CDT will take part in at least one outreach activity. Typical activities include: open days in the Chemistry Department through the 'Outreach Alchemists', engaging with the Oxfordshire Science Festival and participation in the various other activities already in place through the public engagement programme of the Department of Chemistry.
The research output of the students will be disseminated via high impact international publications and lectures; these will be of value to other academics in relevant fields and will be of value in the development of further research funding applications. Outreach activities and research output will also be advertised on a website dedicated to the proposed SBM programme.
This collaborative academic-industrial SBM CDT will have long-term benefit to the chemical industry, including the pharmaceutical, agrochemical and fine chemical sectors. These industries will benefit through: (i) the potential to employ individuals trained with broad and relevant scientific and transferable skills; (ii) new approaches to the investigation of complex biological and medical problems through novel chemistry; and (iii) better and more efficient synthetic methods.
We will link the work of DSTL, and our pharmaceutical and agrochemical partners (GSK, UCB, Vertex, Evotec, Eisai, AstraZeneca, Syngenta, Novartis, Takeda, Sumitomo and Pfizer) through a common theme of synthesis training. The design and synthesis of new compounds is essential for disease treatment and prevention, and for maintaining food security. Synthesis contributes significantly to UK tax revenue and results in sustained employment across a number of sectors. Employers in the finance, law, health, academic, analytical, government, and teaching professions, for example, also recognise the value of the translational skill-sets possessed by synthesis postgraduates, which this programme will provide.
The SBM CDT training programme will adopt an IP-free model to enable completely free exchange of information, know-how and specific expertise between students and supervisors on different projects and across different industrial companies. This will lead to better knowledge creation through unfettered access to information from all academics, partners and students involved in the project. By focussing on basic science, we will engender genuine collaboration leading to enabling technology that will be of use across a wide range of industries.
We will train the next generation of multidisciplinary synthetic chemists with an appreciation of the impact of synthesis in biology and medicine. Their unconstrained view of synthesis will aid in new scientific discoveries leading to new products, which (with appropriate inward investment), can lead to the formation of new companies and new UK employment.
We will, in part through an alliance with the Defence, Science and Technology Laboratory, engage with policy-makers to influence future policy issues involving chemistry such as food security and the rise of antibiotic resistance (both of which are relevant to our programme and are important for society as a whole).
Outreach and public engagement will be a key aspect of our programme; and all students in the proposed SBM CDT will take part in at least one outreach activity. Typical activities include: open days in the Chemistry Department through the 'Outreach Alchemists', engaging with the Oxfordshire Science Festival and participation in the various other activities already in place through the public engagement programme of the Department of Chemistry.
The research output of the students will be disseminated via high impact international publications and lectures; these will be of value to other academics in relevant fields and will be of value in the development of further research funding applications. Outreach activities and research output will also be advertised on a website dedicated to the proposed SBM programme.
Organisations
People |
ORCID iD |
| Stephen Fletcher (Primary Supervisor) | |
| Michael Howlett (Student) |