Synthetic biology – a bridge between fundamental research and application

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    Many parts of the bio-economy reach their limits based on traditional approaches and struggling to meet the challenges of the modern world. For example, the biotechnological sustainable production of bulk chemicals is doing very hard to be competitive with the petrol industry. Drug discovery of natural products is abandoned by large pharmaceutical companies in favour of small chemicals. In contrast to conventional approaches, technological breakthroughs enable deeper exploration and sustainable use of biological resources. The increase in unconventional oil and gas production, the construction of hybrid and/or electric cars are good examples. The vast natural toolbox developed by living organisms over billions of years of evolution undoubtedly contains many undiscovered processes that wait to be explored and harnessed via Synthetic Biology.

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    The concept of Synthetic Biology is based on the ability to freely combine myriads of genes, functional genetic controlling elements, and cellular processes in a simplified chassis organism. Similar to how engineers combine different parts to form lager functional units and products. Synthetic Biology is considered by researchers as an approach or a concept and not as a clearly defined or demarcated field of research. This discipline covers the design and construction of novel biological components, systems, and processes – that are not yet known in nature – together with the re-design of existing biological systems. Although it is already an emerging field, there is an ever-increasing number of applications in the pharmaceutical, chemical, agricultural and energy sectors. Commercial applications tend to focus on creating microorganisms (such as E.coli, baker’s yeast and microalgae) that can synthesize valuable products, such as fuels, food and pharmaceuticals. A notable example is the engineering of yeast cells that synthesise artemisinin, a drug used to treat malaria. In 2012, the World Economic Forum in Davos listed Synthetic Biology as an area likely to have a ‘major impact’ on the global economy in the near future. A report from McKinsey & Company estimates that the impact of this disruptive technology could reach at least $ 100 billion by 2025, enabling tremendous economic growth and job creation for countries that can support a significant synthetic biology-industry, -teaching and -research.

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    Recent DNA deciphering efforts, where the entire (meta-) genomes of bioactive compound-producing organisms have been sequenced, revealed that bacteria (especially actinobacteria) remained a very rich source of new potentially active natural products. Hence, a huge reservoir of bioactive molecules (hundreds of thousands) stays “hidden” in the numerous publicly available bacterial genomes and metagenomes, confirming the strong limitations of conventional approaches for novel drug discovery. Therefore, the major challenge in the field is exploitation of this untapped genomic potential, and its conversion into bioactive chemical entities for their further development as drugs. Unfortunately, the conventional technologies failed to address this challenge. In our department we aim to apply a synthetic biology approaches and to develop a truly functional technology platform for discovery, bioengineering and sustainable supply those hidden in genomes compounds for pharmacological testing.

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     A highly complex and tight regulation is the major reason why these numerous encoding bioactive compounds pathways stay silent in a laboratory conditions. Thousands of various conditions should be tested in order to functionalize these pathways for production of bioactive molecules. This is often inefficient, unpredictable and very laborious. We propose following a synthetic biology driven approach: 1) to capture pathways encoding bioactive molecules; 2) to perform their complete “refactoring” via substitution of every natural regulatory DNA “component” with synthetic genetic control elements, which have highly predictable expression behaviour; 3) to transplant these refactored pathways into simplified reliable bacteria, which will ensure pathway expression resulted in a production of bioactive natural products. Using synthetic regulatory elements that are not under cellular control, allow to bypass natural regulatory networks and forces the expression of natural products encoded pathways. The development of such a generally applicable strategy based on synthetic biology principles of design and construction will enable discovery of thousands of novel bioactive molecules potentially next efficient drugs. We have discovered over 100 new molecules using the heterologous expression of BGCs in our chassis strain and loking forward to many more coming soon.