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Enabling proteins with RNA recognition motifs for synthetic biology and bio-analytics.

Periodic Reporting for period 1 - RNAct (Enabling proteins with RNA recognition motifs for synthetic biology and bio-analytics.)

Reporting period: 2019-01-01 to 2020-12-31

The biological sciences are advancing at breakneck speed, with a flood of unprecedented insights in the functioning and complexity of cells at the molecular level. Even the active engineering of cells is now possible in synthetic biology, where cells can be modified to perform new functions, for example the synthesis of molecules that are otherwise difficult to produce. Synthetic biology promises many such innovations, for example in the field of green energy, and is of crucial importance to the future European bio-economy.

Because of the complexity involved, developments in synthetic biology require a tight interplay between large scale experimental bio-data and computational analysis and modelling. One fundamental way to achieve breakthroughs in this field is through the (re-)design of proteins, the molecular machines that make cells work. By manipulating the function of proteins, new components can be created that can then be inserted into cells, giving them new functions such as the synthesis of a small therapeutic molecule. The economic importance is evident: the emerging synthetic biology market, with related analytical approaches, is predicted to reach tens of billions of euros by 2020, with the bio-analytical and protein engineering markets expected to be worth billions of euros at that point. Currently, education and research in this field are concentrated in the US and the UK, and are less well established in continental Europe.

An urgent need therefore exists to train European researchers in the expertise that drives innovation in synthetic biology and related bio-analytics approaches, and in particular the ability to solve complex challenges in the design of relevant proteins. This requires interdisciplinary skills covering biology, biochemistry and computational sciences combined with the principles of engineering. With the RNAct project, we provide a training programme that ensures that scientists acquire: i) an excellent understanding of both computation and experiment and ii) the ability to solve bio-analytics and synthetic biology challenges at the molecular level.

RNAct addresses this need by combining i) a measured consortium of European participants at the forefront of their research with ii) relevant, well-formulated research with bio-analytics and synthetic biology impact. To do so, we focus on proteins containing RNA Recognition Motifs (RRM) to regulate cells by detecting specific fragments of RNA, the molecules that encode the sequence of proteins. The ability to manipulate these RRMs has wide application potential in bio-analytics and for the creation of synthetic pathways in cells, for example by enabling their activation via small molecule triggers. The 10 Early Stage Researchers (ESRs) trained through RNAct will acquire proficiency for molecular level work on proteins, with an understanding of both experiment and computation. In combination with complementary transversal and entrepreneurial skills training, this will enable the ESRs to constructively contribute to the European bio-economy in both academic and industry settings.
During the first 24 months of the project, RNAct has established a community of 10 ESRs working on designing RRMs and applying them in synthetic biology and bio-analytics, with the ESRs receiving relevant training and ensuring project communication (see The RNAct consortium has created an extensive database of known RRM information, and is analyzing these data to steer the design of new RRMs. This effort is supported by new computational methods to delineate RRM behavior, as well as predicting how they bind RNA. We started a large-scale experiment that will deliver information on the sequence space of RRMs, and how this determines RNA binding. In addition, RRMs are being further investigated and characterized, aiding their inclusion in bacterial cells for post-transcriptional regulation, and in eukaryotic cells for in-cell analysis. Finally, a prototype RNA biochip was already successfully developed for assessing RNA binding.
The RNAct consortium is, by collecting all available RRM information, now able to perform meta-analyses of all RRM information, so uncovering their mode of action. We expect that, combined with in-project generated data and computational methods, this will enable us to start cracking the RRM code and at least partially design RRMs to bind specific RNA fragments by the end of the project. The application of such designed RRMs will be tested in bacteria and eukaryotic cells, with RNA biochips available to test the affinity of RRM binding to RNAs.
Overview of the project