Frontier Manufacturing: Scaling up synthetic biology

Lead Research Organisation: Imperial College London
Department Name: Dept of Bioengineering

Abstract

Synthetic biology has the potential to revolutionise the way we make a host of consumer products from materials and energy to food and medicine. In order for this impact to be realised, we must find the best way to translate laboratory discoveries into operating industrial production processes. The challenge here is to transition from existing factories into the factories of the future.

Today many consumer products are made from fossil resources using synthetic chemistry techniques. In the future we will need to reduce our dependence on petroleum products and move to renewable resources. At the same time, the advent of synthetic biology techniques for rapidly tailoring biological systems for manufacturing purposes will allow us to transition away from synthetic chemistry and into more environmentally friendly production mechanisms using cells. We will tackle the question of how to undergo this transition smoothly by working with our industrial partners on real-world applications in two consumer areas (therapeutics and chemicals manufacturing).

Developing these future biofactories will require the invention of some new generalised technologies to underpin the new manufacturing processes. We will need new biologically based sensors in order to be able to monitor the production processes as they occur to ensure the product quality (and to allow us to intervene if necessary). We will also need new, more robust production cells that can tolerate the high levels of compounds they make and new microreactors and/or compartmentalisation strategies for using enzymes when whole cells are not required. Because the transition will not happen overnight, we will need to develop intermediate production methods that combine biological and chemical catalysts. This will require solvents that are less toxic to proteins and cells and proteins that are engineered to be more robust in the presence of chemicals. In order to develop processes that are economical and efficient (minimal energy and water usage), we will create computer models to compare alternatives. The most promising processes will be implemented in the factories of our industrial partners.

We have chosen two challenge areas in which to test our new technologies. The first is healthcare, specifically the manufacture of medicinal compounds and therapeutic proteins. These are already largely made using biological systems, but the existing processes are expensive and complicated. Also, in the future, it would be more efficient to make these medicines as and when they are needed (point-of-care manufacture). Our goals are to make simpler, more cost effective, point-of-care manufacturing systems using a combination of the above mentioned platform technologies: enzyme microreactors, specialised cells, and biosensors.

Our second target is to produce bulk chemicals without the need for petroleum inputs. This will require us to adjust our manufacturing techniques for renewable inputs (such as biomass) and to develop new processes that use biology and/or environmentally friendly chemistry to do the conversions. Synthetic biology has never been attempted on such a large scale. Our challenge will be to adapt our parts, devices, and systems to operate at this level.

The overall outcome will be novel, cost effective, energy efficient, and sustainable routes to therapeutics and chemicals.

Planned Impact

The development of synthetic chemistry in the 19th and 20th centuries resulted in many of the major industries of today. These industries largely rely on oil as their basic feedstock. The fragility of oil supply has led a need to reengineer the chemicals industry to use bio-based feedstocks. Synthetic biology can make a major contribution to this.

At Imperial College's Centre for Synthetic Biology and Innovation, together with national and international colleagues, we have been developing platform technologies which are applicable across a range of industrial fields. This comprises novel wet lab techniques for DNA assembly, BioPart characterisation and Host Cell (Chassis) development - as well as a web-based synthetic biology information system (SynBIS) comprising a professional registry of BioParts, Models and BioCAD design tools. Imperial's Departments of Chemical Engineering and Chemistry are both internationally renowned for their industrially-relevant innovation in chemicals manufacturing, process development and design, and the translation of this to industrial application. This project is to address the challenge of taking synthetic biology from the laboratory bench to the chemicals manufacturing plant. We will ensure this by cutting edge research and innovation, translation underpinned by deep industrial user engagement and the development of future leaders, as described in the Case for Support and Pathways to Impact Statement.

We anticipate our work will benefit a wide range of stakeholders including: synthetic biologists, chemical and energy companies, materials manufacturers and the broader chemical industries, as well as consumers interested in new products developed through the exploitation of synthetic biology. Our proposed project will demonstrate to this broad base of stakeholders the opportunities and benefits of novel hybrid chemo-biological processes, and compute performance benchmarks by which novel processes can be compared against existing process chains.

In order to ensure this impact, we have already involved several industrial partners (GSK, Shell, Lonza, Dr Reddy) as initial stakeholders in our research programme. Representatives from each of these companies will be closely involved in helping to shape and critique our activities, advising us on pathways to commercialisation and ensuring we maximise the impact of our research efforts.

As this research is primarily aimed at developing manufacturing processes using synthetic biology, we anticipate a substantial impact on the future landscape of the UK manufacturing sector. The material routes and practices developed in this type of research represent potential economic impact by developing secure routes of material and chemical manufacturing within the UK. Breaking our dependence on fossil reserves will also necessarily create new manufacturing industries and also reduce our dependence on imported goods. Introducing novel synthetic biology practices will also revolutionise the existing manufacturing industries.

There is great training potential within this project. As we will be employing 12 full-time researchers in the programme, we will be furthering the dissemination of synthetic biology principles into the employment sector. This will influence future manufacturing directions as the propagation of these future research and development leaders into industry is inevitable.

The extensive timeline of this programme (five years) will enable us to have a sustained impact on manufacturing practices and policies, as we will be able to extend our vision into industry (through our project partners) and public policy (through our advisory institutes). The value of these goals cannot be overstated - the impact of academic research can only be realized if the support of government agencies and the UK public is evident. This requires long-term commitments to the research principles we have outlined within this programme.

Publications

10 25 50
 
Description The purpose of the project was to address the key issue of whether or not it would be possible to develop alternative methods for processes and products based on an alternative industrial model. The traditional industrial model, which forms the basis of many of today's industries, uses oil-based feedstocks as input, feeding through synthetic chemistry to processes and products. The alternative is to develop a low carbon industrial model that uses bio-based feedstocks as input, feeding through synthetic biology to processes and products. Synthetic biology has the potential to revolutionise the way in which we make a wide range of products from materials to energy, food and medicine. This requires a move away from synthetic chemistry-based processes into more environmentally friendly production mechanisms typically using cells.

The approach tackled in the project involves the development of future bio factories and this, in turn, required the invention of some new generalised technologies to underpin the new manufacturing processes. In the project we chose two areas in which to test our new technologies. The first of these is healthcare and, specifically, the manufacture of medicinal compounds and therapeutic proteins. The advantage was that these are largely made using biological systems, but the existing processes are expensive and complex. The goal was therefore, to make simpler and much more cost-effective manufacturing systems, using a combination of platform technologies, enzyme micro-reactors, specialised cells and biosensors.

The second objective was to produce bulk chemicals without the need for petroleum imports. This required the adjustment of manufacturing techniques for renewable inputs, such as biomass. In addition, the development of new processes that use biology and environmentally friendly chemistry to do the conversions. The aim, which was largely met was to produce bio parts, devices and systems that could meet this challenge.

The strategic approach which was used is based on the fundamental concept underlying synthetic biology, i.e. platform technology that can be applied to a range of applications. The project was, therefore, divided into three separate platforms namely P1, P2 and P3.

P1. This involved strategies for designing and optimising bio-based unit operations including biosensors for process control, genetic rewiring tailored production strains, and complex modular and enzymatic systems for manufacturing user-defined enzymatic pathways.
P2. Comprise the development of hybrid process systems through biologically friendly solvent design and modifications to biological systems to increase of intolerance.
P3. This involved process development, intensification, scale up and optimisation strategies for artificial membrane compartmentalisation and cell extracts. These platforms are then applied to two areas that operate at different ends of the manufacturing scale.
C1. The production of novel therapies (lower- volume, high value added products)
C2. Synthesis of commodity chemicals for renewable feedstocks (high-volume, low value-added compounds).

The key findings associated with the project fundamentally revolve around the development of platforms. Within synthetic biology and the project this has to a significant extent revolved around the development of Biofoundry technology. This enables significant levels of automation to be applied to synthetic biology processes - to increase reliability and reproducibility. This, in turn, has fed through to SynbiCITE applications involving a number of companies, as well as producing fundamental development that will be applied in the new joint venture with Manchester University Bio Manufacturing Research Hub. The approach has allowed much more reliable research methods and skills to be developed in the context of the Imperial College bio foundry (the London Biofoundry). The whole bio foundry approach, which uses material from the project, has produced a paradigm shift in the ability to develop biologically based processes, which are much more reliable and robust.

In relation to training, there are two avenues that have developed from the project, as well as other sources. These are: the development of the joint Centre for Doctoral Training in Bio design. (The CDT is a joint venture between Imperial College, Manchester University and University College London.) The other training development is the ability to train researchers on the use of the Biofoundry.

Key findings were the development of:

• Optimised chemistry, biology and engineering
• Robust biocatalysts
• Robust organisms - tolerant to, for example, ionic liquids
• Biocompatible, chemical " accelerants"

Three examples are the development of:

1. A model of an ionic liquid- tolerant bacterium for converting hydrolysed biomass into biofuel.
2. Synthetic reactor system to modify glycan structures of protein therapeutics
• Control product quality
• Modular design for different structures and therapeutic applications.
3. Vesicle Reactors/Artificial "Cells "
Systems are important because many synthetic biology based systems rely upon intracellular reactions. The alternative is to develop methodology which is based on a cell-free approach. There are, however, instances where a halfway house is appropriate. Here the vesicle reactor/artificial cell approach can be ideal because it allows cell like activity without the complication of natural intracellular control mechanisms.
Exploitation Route In the opinion of the project team, the original objectives were met. However, it is important to point out that this is an ongoing process because of the interaction between the project group, SynbiCITE and a range of companies that SynbiCITE supports - in terms of their growth. It is, therefore, extremely likely that much of the work of this the project will be developed further through companies, as well as, through the Bio Manufacturing Research Hub. For further general details please follow the links: https://futurebrh.com/
Sectors Chemicals,Digital/Communication/Information Technologies (including Software),Education,Environment,Healthcare,Manufacturing, including Industrial Biotechology

URL http://www.synbicite.com
 
Description Over the last two or three years there has been significant work on the development of an industrial strategy for the UK - e.g. The industry strategy Green Paper and the Life Sciences Industrial Strategy. These and other documents have identified the importance of the bio economy. Recent Government estimates (Growing the Bioeconomy, 2018) place the value of the bio economy at around £220b GVA (2015) and set to grow to £440b by 2030. Many observers believe that this will only be possible through the type of disruptive technology that synthetic biology represents. Within the project, two areas were chosen to test our new technologies. The first is healthcare, specifically the manufacture of medicinal compounds and therapeutic proteins. These are already largely made using biological systems, but the existing processes are expensive and complicated. Also, in the future, it would be more efficient to make these medicines as and when they are needed (point-of-care manufacture). Our goals have been to make simpler, more cost effective, point-of-care manufacturing systems using a combination of platform technologies: enzyme micro reactors, specialised cells, and biosensors. In terms of impact, one example of our research projects that is yielding fantastic results is the development of vesicle bioreactors for protein synthesis. A second target was/is to produce bulk chemicals without the need for petroleum inputs. To do this we are adjusting our manufacturing techniques for renewable inputs (such as biomass) and developing new processes that use biology and/or environmentally friendly chemistry to do the conversions. Synthetic biology has never been attempted on such a large scale. The challenge is to adapt the synthetic biology design, build test and learn (DBTL) paradigm to adapt our parts, devices, and systems to operate at the levels of the subprojects within the overall project. The overall aim, in terms of impact, is to achieve cost effective, energy efficient, and sustainable routes to therapeutics and chemicals. Have the findings from this award contributed to any non-academic impacts? It is still relatively early for the full implementation of the findings of the project; however, one example is the creation of a new company, supported by SynbiCITE. The principal founder is Prof Jason Hallet (one of the Co-Is on the project). Every year, Scientific American uses a group of technology experts to identify important emerging technologies. Prof Hallett's new company, Lixea, a result of the project, was identified as a major disrupter in the field of bio plastics. https://www.lixea.co/ Another aspect of the project contributing to non-academic impacts is that the work of the project has been fed through SynbiCITE, which is a partner in the Manchester University led Biomanufacturing Hub - a major EPSRC funded project. How have your findings been used? The basis of the work involves on separating plant components to develop more sustainable plastics using waste materials. The Lixea this has worked, in terms of its development, with SynbiCITE. He had supported the company in various way; for example, through participation in the centre's Lean LaunchPad course. Lixea is an Imperial College spin-out company that is developing an innovative biomass fractionation process using low-cost ionic liquids to produce degradable bio plastics. This is an alternative approach to the used of oil as a feedstock. The company's BioFlex process uses waste biomass (agricultural byproducts and would waste), as well as biomass grown for the purpose, to produce bio plastics. The company has recently been successful in obtaining a significant EU grant for the development of the process. The work and findings of the project have also been incorporated into the curriculum of the new BioDesign Centre for Doctoral Training (Imperial College, Manchester University and UCL).
Sector Chemicals,Digital/Communication/Information Technologies (including Software),Environment,Healthcare,Manufacturing, including Industrial Biotechology
Impact Types Societal,Policy & public services

 
Description A Synthetic Biology Roadmap for the UK
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact This report provides the vision and direction for supporting a world-leading synthetic biology community in the UK. Produced by an independent panel of experts for the government's Department for Business Innovation and Skills, it sets out a shared vision for realising the potential of synthetic biology in the UK. The roadmap aims to deliver a synthetic biology sector that is cutting edge; economically vibrant, diverse and sustainable; and of clear public benefit. Recommendations in the roadmap also provide a compass-bearing for the synthetic biology community, helping to align interests towards future growth opportunities, whilst identifying the resources and support needed to accelerate progress in the shorter term.
URL http://www.rcuk.ac.uk/publications/reports/syntheticbiologyroadmap/
 
Description PAS 246 - Use of standards for digital biological information in the design, construction and description of a synthetic biological system - Guide
Geographic Reach Europe 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
Impact PAS 246 - Use of standards for digital biological information in the design, construction and description of a synthetic biological system. Is a standard and guide to the development and use of data pertinent to bio-manufacturing and biotechnology
URL http://shop.bsigroup.com/ProductDetail/?pid=000000000030303883
 
Description UK Synthetic Biology Strategic Plan 2016 - Biodesign for the Bioeconomy.
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact Minister for Life Sciences George Freeman MP visited SynbiCITE at Imperial College London, the UK innovation and knowledge centre for synthetic biology, on 24th February 2016 to announce the release of the UK Synthetic Biology Strategic Plan 2016 - Biodesign for the Bioeconomy. This strategic plan, published by the Synthetic Biology Leadership Council (SBLC), aims to accelerate the commercialisation of synthetic biology products and services with clear public benefit, building upon the strength of the UK research base. It focuses on five key areas of strategic importance: Accelerating industrialisation and commercialisation Maximising the capability of the innovation pipeline Building an expert workforce Developing a supportive business environment, and Building value from national and international partnerships. It builds on the recommendations made in the Synthetic Biology Roadmap for the UK, which was first published by Innovate UK in 2012. The roadmap led directly to major funding and policy activities, including the establishment of new synthetic biology research centres, the Innovation and Knowledge Centre at SynbiCITE, DNA synthesis facilities, training centres and a seed fund for innovative companies. In addition, the Synthetic Biology Leadership Council (SBLC) was founded to manage the continued growth of this field. During 2015, the Synthetic Biology Leadership Council (SBLC) consulted a broad cross-section of businesses and the research community to develop this new strategic plan, building upon the successes of the 2012 roadmap.
URL https://connect.innovateuk.org/documents/2826135/31405930/BioDesign+for+the+Bioeconomy+2016+DIGITAL+...
 
Description Imperial College Festival 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Public introduced to new emerging disruptive technology - Engineering Biology. Engineering of Biology to make really useful stuff. For example, seeing virtual reality labs and an introduction to new science that affects every day life. Including children's competitions, interactive technologies for all.
Year(s) Of Engagement Activity 2015,2016
URL http://www.imperial.ac.uk/festival/about/festival-2016/
 
Description Imperial College London IB and SB Technology Showcase 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact The event showcased work going on at Imperial in the area of Engineering Biology. The event was hosted by the Synthetic Biology Hub and the Industrial Biotechnology Hub. Keynote talk on UK Government Strategy for Engineering Biology was Professor Janet Bainbridge OBE, and were further presentations from leaders in the field from industry and Imperial.
Year(s) Of Engagement Activity 2017
URL http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/eventssummary/event_9-5-2017-11-29-54
 
Description Leadership Excellence Accelerator Programme (LEAP) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Each year about twenty Fellows - emerging leaders working in diverse areas of biotechnology - are selected to participate.

LEAP envisions catalysing a next generation of leaders in synthetic biology by providing the environment to learn skills for engaging a broad range of stakeholders in the development of the field with a strong ethical foundation for the future.
LEAP does this by:
Investing in the individuals who will ultimately shape and govern this diverse, growing and globally distributed technology.
Providing them with new tools and networks essential to achieving their visions for promoting innovation responsibly in practice.
Acting as a sustaining nexus of resources and support as leaders assume their roles.
Year(s) Of Engagement Activity 2014,2015,2016,2017
URL http://www.synbicite.com/knowledge/leap/
 
Description Synapse Connect Meeting 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Synapse is a student driven non-profit organisation in a the Copenhagen area that creates events, workshops and networking opportunities for students and young professionals with an interest in perusing careers in a life science environment. SynbiCITE, together with the Synthetic Biology Imperial College (SynBIC) organised talks with regard to synthetic biology in the UK. Professor Kitney spoke to the group and they were given a tour of the SynbiCITE labs. The Imperial College iGEM team gave a talk on their 2016 iGEM competition win.
Year(s) Of Engagement Activity 2017
 
Description iGEM competition and jamboree (UK & US) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact The iGEM Competition is the premiere student team competition in Synthetic Biology..

For over 10 years, iGEM has been encouraging students to work together to solve real-world challenges by building genetically engineered biological systems with standard, interchangeable parts. Student teams design, build and test their projects over the summer and gather to present their work and compete at the annual Jamboree.

Participation in the iGEM competition empowers teams to manage their own projects, advocate for their research and secure funding. Teams are also challenged to actively consider and address the safety, security and environmental implications of their work. The 2016 Imperial Team led by Dr Guy-Bart Stan and Dr Karen Polizzi, together with Profs Kitney and Freemont won the overall competition at the Jamboree, with their project which was entitled "Ecolibrium - developing a framework for engineering co-cultures". Profs Kitney and Freemont were judges at the 2017 Jamboree.
Year(s) Of Engagement Activity 2013,2014,2016
URL http://2016.igem.org/Main_Page