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PROMYS Report Summary

Project ID: 613745
Funded under: FP7-KBBE
Country: Denmark

Periodic Report Summary 3 - PROMYS (Programming synthetic networks for bio-based production of value chemicals)

Project Context and Objectives:

The partners of PROMYS have merged scientific and commercial aspirations with a clear vision to accelerate the bio-based revolution of the USD 4 trillion chemical industries. In fulfilling this ambition, PROMYS will develop, validate and implement a novel synthetic biology platform technology that drastically accelerates the construction, optimization and performance of cell factories by enabling industrial users to impose non-natural objectives on the engineered cell factory. Such non-natural objectives include overproduction of target chemicals at high yields and rates, a trait that normally conflicts with natural cellular objectives of survival and high growth rate. The PROMYS framework integrates the forward-engineering tools and concepts of synthetic biology for system design with identification of the most advantageous parameters through self-selective cycles of biological optimization. Our work program will enable the industrial user to re-engineer biological machinery for human defined objectives by overruling the natural inclinations of biological systems. Through its endeavours PROMYS will profoundly innovate contemporary metabolic engineering with a strategic impact on industrial applications within the chemical industry.

To realize our goal we will develop methods for the de novo design of what we term ligand responsive regulation and selection systems, which are robust biomolecular circuits for controlling cellular fate based on intracellular metabolic cues. Such synthetic cellular networks will be used to impose non-natural selective pressure on the host cell. This selective pressure will be defined by the metabolic engineer to serve specific objectives of his/her application. Coupling selective pressures to the construction and optimization of metabolic processes is not novel; in fact this is the basis for the evolution of all biochemical processes within the natural world. The novelty of PROMYS results from integrating the principle of user defined self-selective cycles of biological optimization within the synthetic biology framework and applying it to solve major challenges within metabolic engineering.

In addition to the above-mentioned technological opportunity, an important driver for the envisioned concept is the significant market demand: The bio-based segment of the chemical industry currently constitutes a USD 90 billion market, projected to reach USD 180 billion by 2020. Thus, innovative technologies enabling this transition will be of substantial commercial value.
To address the clear market need, PROMYS will exploit the technological opportunity to develop and apply ligand responsive selection systems. Specifically, PROMYS will address three major challenges in metabolic engineering that limit the development of new cell factories:
1) Synthetic pathway construction
2) Cell factory optimization
3) Control of populations during fermentation

Project Results:
In the first three years of the PROMYS project has achieved significant scientific progress has already been achieved as highlighted below:

1. Characterization of input material for ligand responsive selection systems. An important objective for this period was to enumerate both RNA and protein based biosensors that could be deployed as ligand responsive selection systems. This has been achieved and databases have been established that provide an overview of existing biosensors.
2. Development of ligand responsive systems for the key metabolites of the project.
3. The basic scientific work on ligand responsive selection systems is progressing well and several new approaches to achieve robustness and evolutionary stability have been tested and validated. New approaches generating synthetic RNA circuits have shown promise and continue to be developed.
4. Finally, the cell factory construction work has been initiated for all chemical products selected for the project, we have already achieved production of some of the target chemicals.
5. We have constructed several cell libraries to be interrogated for optimized enzyme function, new synthetic pathways, and cell factory optimization. Interrogation of these libraries enable discovery of novel enzymatic function, including transporters mined from metagenomics samples.
6. We have constructed synthetic networks that enable control of cell fate in response to intracellular cues and used those to improve production titers.
From the perspective of exploitation and dissemination the work has proceeded well and an exploitation and dissemination plan has been written and approved by all parties of the project. Also, the project website has been established ( Several early results have already been published and the results are being further disseminated through conference attendance at international meetings. A business development officer has been recruited to ensure adequate exploitation of project results in the final project year.

Potential Impact:
The project outcomes will contribute towards the expected impacts listed in the work programme topic KBBE 2013.3.6-02. With respect to technology - including the advancement of the research in the field of synthetic biology (scientific breakthroughs) - impacts include the creation of innovative tools and methods for biotechnology applications, and development of engineered biological systems to accelerate process design. Secondly, PROMYS has impacts which increase of the industrial competitiveness, the creation of new economic opportunities, the reduction of time-to-market, the increase of consortium SMEs competitiveness and benefits. The technologies that will be developed in PROMYS, will find their application mainly in the sector of fine and specialty chemicals. Speciality and fine chemicals are used in a wide range of industries, including the pharmaceutical and nutraceutical industry, the food and beverage industry, and the cosmetics industry. The global market for fine and specialty chemicals (which potentially can be replaced by biotechnological processes) is forecast to have a value higher than USD 900 billion in 2016. The bio-based chemicals market was valued at USD 75B in 2010 and it is expected to grow at a CAGR of 9% to USD 180B in 2020. Accordingly, PROMYS will have both technological and commercial impacts.
Technological outputs:
- Methods for identifying new synthetic pathways
In this project, the general strategies for synthetic pathway construction will be developed using theophylline as proof of concept molecule. Nevertheless, once validated PROMYS technology for synthetic pathway construction can be applied to several other molecules that have not previously been produced in cell factories. The benefit of using ligand responsive selection systems compared to existing technologies is that optimal pathways can quickly and efficiently be identified, substituting the labor intensive and time-consuming analytical screening.
- Strategies for cell factory optimization
In PROMYS, strategies for cell factory optimization will be developed using thiamine as an initial proof of concept. However, cell factory optimization using ligand responsive selection systems and flux-redistribution could be deployed for the optimization of cell factories for most chemicals.
- Novel genetic devices for controlling fermentation
Genetic devices developed in PROMYS for the control of cellular phenotypes during fermentation will have a significant commercial potential and could be used for controlling fermentations for production of any chemical. The technology will be particularly well suited for optimization of production processes for which the high yielding cell factory has a substantially reduced fitness as a result of the chemical production.
Commercial outputs:
- New cell factories for a number of different compounds will be developed with the participating SMEs. Each cell factory comprises the seed for a biobased process withmultimillion Euro revenue potential.
- New technology platforms for cell factory development and optimization will be developed with the participating SMEs. These platforms can be deployed on a range of compounds and can help boost the competitive edge of the European biobased industry.

List of Websites:

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