September 22, 2018

How Manchester’s SYNBIOCHEM is harnessing the power of synthetic biology to scale up the production of chemicals and materials

SYNBIOCHEM

This story is brought to you by our sponsor SynbiCITE, which is accelerating the commercialization of synthetic biology applications. To learn how SynbiCITE is nucleating a sustainable UK economy, visit www.synbicite.com.

The city of Manchester, UK was at the heart of the 19th-century industrial revolution, when technological advances transformed the industrial landscape and impacted  all aspects of everyday living. During this time, with the transition to new mechanical and chemical manufacturing processes, industrial production increased tremendously, bringing wealth and power to Great Britain as an economic global leader.

Now in the 21st Century, with the results of industrialization, technological and medical developments, we are faced with a different set of societal challenges, including: an ever-increasing and ageing global population, affordable health care, resource efficiency, food security, climate change, and energy shortages. Coupled to this is the growing recognition that we need to change our reliance on petrochemicals and to address the global environmental impact of our production processes and waste products. The development of “cleaner, greener” sustainable production processes through low carbon technologies and the efficient use of resources, towards a circular bio-based economy and cleaner economic growth, is one of the greatest industrial opportunities of our time.

Bio-based chemical production processes are already delivering major economic impact for industrial biotechnology (IB), but there is huge potential for the tools and techniques of synthetic biology to dramatically enrich and expand bio-based production routes. Once again Manchester is leading this 21st Century bio-industrial revolution, building on a proud tradition as the historical home of chemical engineering, and in pioneering the use of biological fermentation processes for chemicals production (initiated by Chaim Weizmann). IB is a major research strength of the University of Manchester, with pioneering discovery, interdisciplinary collaboration and cross sector partnerships. Centred in the Manchester Institute of Biotechnology (MIB), there is a focus on the biological production of diverse high-value chemicals and materials, and the valorization of waste through the development and application of key enabling technologies — synthetic biology in particular.

In 2014, Manchester received major synthetic biology research funding (>£10M,) for SYNBIOCHEM, a Synthetic Biology Research Centre for fine and speciality chemicals production, as part of a National UK investment strategy to establish a comprehensive network of research centres, DNA Foundries, Centres of Doctoral training and a National Innovation and Knowledge Centre (SynbiCITE). This ongoing strategy is aimed to ensure that the UK is positioned at the forefront of future sustainable IB and bio-manufacturing developments in the drive towards the global bio-economy.

The SYNBIOCHEM Centre was built upon the world-leading fundamental research of the University of Manchester’s Institute of Biotechnology (MIB, www.mib.ac.uk), where it unites expertise from across the foundational sciences, including biological catalysis, analytics, systems biology and computational modelling to deliver a bio-engineering foundry. Co-directed by Professors Nigel Scrutton, Eriko Takano and Nicholas Turner, the Centre unites 29 research groups supported by an expert team of Senior Experimental Officers to implement the Centre’s challenge-led collaborative science programmes. This next generation synthetic biology research is directed towards understanding, harnessing and directing the inherent biosynthetic capacity of microorganisms towards the production of diverse novel speciality chemicals, and to deliver high concentrations of industrially important compounds with increasing predictability and speed. By coupling new capabilities in the rational design of genetic circuits and pathways for the production of fine chemicals, and the targeted discovery of new chemical entities with potential bioactive properties, we will move towards a “dial-a-molecule” capability, for a wide range of IB applications, including: new products and intermediates for drug development, agrochemical and new materials for sustainable bio-manufacturing.

Just as the introduction of new machinery transformed production processes in the first industrial revolution, automation and robotics are transforming the way we are conducting research in the 21st Century. Manual laboratory techniques are being replaced with automated liquid handling robotics, allowing accurate high throughput methodologies and screening. In SYNBIOCHEM, automated “Build” capabilities are complemented by advanced computational methods for intelligent in-silico “Design” (modelling, design of experiments, data screening and machine learning), coupled with high-end “Test” analytical capabilities (for accurate identification and quantification of our chemical targets) which is transforming our capability to rapidly provide Design-Build-Test-Learn cycles for the engineering of biology.

SYNBIOCHEM

SYNBIOCHEM’s early focus has been to innovate and integrate technology developments to advance academic discovery science in the chemicals production sector, and to establish an integrated suite of technologies founded upon the application of predictive methods in synthetic biology. The realization of this vision has delivered an automated Design-Build-Test-Learn pipeline for enhanced microbial production of fine chemicals and to accelerate the evolution of enzymes, biological production routes and microbial production strains. The successful implementation of the SYNBIOCHEM pipeline (Figure 1), recently demonstrated (Nature Communications Biology, 2018) for the microbial production of flavonoids and alkaloids in E. coli, represents a major Centre achievement. Following further optimization and automation, the Centre is now confident its pipeline capabilities can be applied to facilitate rapid optimization of bacterial strains for the production of any chemical compound of interest.

The strength of SYNBIOCHEM and its location within the MIB enables it to complement its synthetic biology with deep understanding of catalysis/chemical science, mechanistic and systems biology, supported by world-class analytics, data management, computation and informatics – all globally recognised strengths of the MIB. This enables SYNBIOCHEM to rapidly expand, implement and integrate its frontier knowledge of enzyme design, directed evolution, and retrosynthetic methodology into its synthetic biology workflows, with deep chemical expertise that is openly shared and utilized to deliver cross-disciplinary programmes which pulls away from automated “cut and paste” biology that is often a central feature of foundries.

Recent SYNBIOCHEM research programmes have benefited from its interdisciplinary, international and inter-sector research collaborations, and have already delivered new intellectual property, including the development of tools and microbial hosts for the production of a range of important high value chemicals from pharmaceuticals, flavors, and fragrances to biofuels and materials. These are supported by developing in silico design tools and assembly methods that underpin the rapid construction and evolution of new parts and pathways (e.g. SensiPath, RetroPath2.0; Selenzyme, Biochem4j, PartsGenie, GeneGenie and Codon Genie) through new approaches to directed evolution (e.g. GenOrator library design).

SYNBIOCHEM

SYNBIOCHEM is also aiming to de-risk synthetic biology-based bio-manufacturing strategies at early stages of translation by co-development with stakeholders (e.g. corporates, SMEs), and remove barriers to the development and adoption of synthetic biology based bio-manufacturing. From the offset, SYNBIOCHEM set an ambitious goal to commercialize its research activity through Intellectual Property (IP) disclosures and patents, with subsequent licensing agreements available to companies. This has been achieved by working closely with industry partners and has provided new bio-parts and production platforms that are delivering new routes to antimicrobial compounds, drug precursor chemicals, flavors, and fragrances (e.g. pravastatin, menthol and monoterpenes), new component enzymes for fuels production and biofuels (e.g. bio-propane).

An example of successful translation is the Manchester University spin-out company C3 Bio-Technologies Ltd, set up for the commercial bio-synthetic production of propane, and spearheaded by the MIB/SYNBIOCHEM Director, Nigel Scrutton, and Mike Smith, Director of Pressure Tech Transport Services Ltd, a specialist regional supplier of petroleum gas (LPG). By continuing to innovate in synthetic biology technology areas, and by growing networks/partnerships to support early stage translation, SYNBIOCHEM aims to remain competitive and make an important contribution to the industrialisation of biology in the UK with global impact. In this respect, the Centre has benefited from SynbiCITE entrepreneurship training (4-day MBA) and is exploring the further translation of its research outputs towards commercialization.

The societal consequences of the first industrial revolution were widespread and changed the social structure of Britain.  It is now recognized that for the early introduction of modern technologies an early understanding of the potential impact of our research on society is important. The SYNBIOCHEM Centre has embedded Responsible Research and Innovation research in its activities, to facilitate collaboration and deliberation to support the Centre to anticipate, prepare for, and mediate impacts of synthetic biology technologies in society, economy, and the environment. RRI work programs include: real-time assessment of synthetic biology research, applications and innovation, sustainable industrial systems including constructive life-cycle analysis, ethics and deliberation to anticipate potential risks, ethical, and regulatory concerns, and collaborative development. An example of this has been a real-world case study of compounds (e.g., menthol) being produced at the Centre, that examined a series of potential ethical, environmental, and social issues involved in the transition from natural and chemical to synthetic biology production. Other issues explored by the RRI group include a horizon scan of emerging issues in engineering biology, public value propositions in synthetic biology patents, roles of funding and interdisciplinarity, and the societal and business models of synthetic biology start-ups.

The future focus SYNBIOCHEM is to innovate and integrate technology developments to advance academic discovery science in the chemicals and materials sectors. This will be achieved by working closely with industrial partners and academic researchers from across the globe. As such, SYNBIOCHEM actively seeks to expand the scope and influence of synthetic biology through engagement with wider scientific and engineering communities.

SYNBIOCHEM, the Manchester Synthetic Biology research Centre, harnessing synthetic biology approaches to engineer microbes for rapid, predictable fine and speciality chemicals production. To learn more about SYNBIOCHEM’s activities visit: www.synbiochem.co.uk

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