13TSB_SynBio - Rapid Engineering of Cellular Factories

Lead Research Organisation: University of Manchester
Department Name: Chemistry

Abstract

This is a collaborative R&D project, with the goal of demonstrating the rapid creation of bacterial cellular factories. Over the
next 10-20 years the global chemistry using industry is predicted to undergo a major transformation. Driven by the need to
develop processes that are both economically and environmentally sustainable, the industry will increasingly turn to
renewable feedstocks for the manufacture of a growing range of products. It is estimated that by 2020 approximately 20%
of existing chemical processes will be based on Industrial Biotechnology (IB), and advanced synthetic biology and
bioprocesses.

Within this project we intend to combine several novel technologies, including biopumps, riboswitches, and statistical
process optimization to create engineered micro-organisms which are able to selectively import small molecules, convert
them via short synthetic pathways, and export the finished molecules on a whole cell basis. This methodology has the
potential to revolutionize biocatalysis and IB, and additionally constrains the technical risk, as the use of biopumps allows
the optimization of only short synthetic pathways, rather than utilizing an organism's native metabolic pathways from basic
feedstocks. The outputs from this grant will lead to alternative sustainable chemical production process, with the potential
to reduce the reliance on petrochemically derived feedstocks. This research project will also generate technology and
knowledge that will help maintain the UK's competitive edge, and will produce highly trained and skilled research
personnel.

Technical Summary

This is a collaborative R&D project, with the goal of demonstrating the rapid creation of bacterial cellular factories. Over the
next 10-20 years the global chemistry using industry is predicted to undergo a major transformation. Driven by the need to
develop processes that are both economically and environmentally sustainable, the industry will increasingly turn to
renewable feedstocks for the manufacture of a growing range of products. It is estimated that by 2020 approximately 20%
of existing chemical processes will be based on Industrial Biotechnology (IB), and advanced synthetic biology and
bioprocesses.

Within this project we intend to combine several novel technologies, including biopumps, riboswitches, and statistical
process optimization to create engineered micro-organisms which are able to selectively import small molecules, convert
them via short synthetic pathways, and export the finished molecules on a whole cell basis. This methodology has the
potential to revolutionize biocatalysis and IB, and additionally constrains the technical risk, as the use of biopumps allows
the optimization of only short synthetic pathways, rather than utilizing an organism's native metabolic pathways from basic
feedstocks. The outputs from this grant will lead to alternative sustainable chemical production process, with the potential
to reduce the reliance on petrochemically derived feedstocks. This research project will also generate technology and
knowledge that will help maintain the UK's competitive edge, and will produce highly trained and skilled research
personnel.

Planned Impact

WHO WILL BENEFIT: Platform and fine chemical companies, biotech companies and contract manufacturing organisations
charged with producing fine and platform chemicals on the multi-kilo and -ton scale, in particular the project partner
Synthace. Additionally, many chemical companies that employ biocatalysts, such as DSM, Lonza, BASF and Dr. Reddy's,
could also benefit from the technologies developed here. Similarly, oil companies such as Shell and BP have invested
heavily in synthetic biology programmes to engineer bacteria to produce new biofuels, where new-engineered microbial
factories would be equally important. Any number of these companies could benefit through licensing agreements to use
new systems based on the technologies developed in this project.

HOW WILL THEY BENEFIT: We will actively seek to communicate our findings to the wider community through scientific
meetings and scholarly publications (We consistently publish in top journals such as: JACS, PNAS, Angew. Chem. &
Nature Chem. Biol.). However, in order for the technology we develop to become widely adopted, particularly in industry, it
will be important to first secure any intellectual property rights for all new inventions we discover. As the research
progresses and our relationships with interested commercial partners develop, and whilst working within the conditions of
the grant, we will seek to commercially exploit these new technologies and license on IP for use in industrial-scale chemical
production processes. Improvements in cell line platform development and bioprocess efficiency, generated from this grant,
could lead to alternative sustainable sources for chemical production, and reduce the reliance upon petrochemical
feedstocks, leading to associated potential environmental benefits. This research project will also generate technology and
knowledge that will help maintain the UK's competitive edge and will produce highly trained and skilled research personnel.

Publications

10 25 50
 
Description Foundational technology development in the Synthetic biology area has been developed during this project by consortium members from The University of Manchester - these tools are now being applied in number of further research projects to allow us to better control and engineer micro-organisms to have desirable traits for producing chemicals and proteins of industrial and clinical importance.
Exploitation Route The project achieved its objective and developed a biosynthetic route to the target high-value chemical. However during the course of the project external economic factors meant that the target chemical was no longer a commercially feasible target and so the primary findings have not been taken forward as planned. However, the technology developed is now being applied in number of further research projects to allow us to better control and engineer micro-organisms to have desirable traits for producing chemicals and proteins of industrial and clinical importance.
Sectors Chemicals,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description Has led to the adoption of new working practices within industrial collaborators UK-based R&D facility, which has led to new business opportunities.
Sector Chemicals,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description BBSRC-FAPESP pump-priming award
Amount £35,000 (GBP)
Funding ID BB/L026244/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 08/2014 
End 07/2016
 
Description David Phillips Fellowship
Amount £1,101,823 (GBP)
Funding ID BB/K014773/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 11/2013 
End 10/2018
 
Description IB Catalyst - Early Stage Feasibility
Amount £121,512 (GBP)
Funding ID BB/M011259/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2015 
End 03/2016
 
Description Collaboration with CMO for biologics production 
Organisation Cobra Biologics
Country United Kingdom 
Sector Private 
PI Contribution We have contributed IP, know-how, and research expertise to this collaboration
Collaborator Contribution The partners have contributed industry R&D and know-how
Impact Too earlier to say, the collaboration has led to successful joint grant funding.
Start Year 2013
 
Description Collaboration with International biopharma company (2017- on going) 
Organisation Novo Nordisk
Country Denmark 
Sector Public 
PI Contribution Following on from research data present and US conference, this international biopharma companies made contacted and expressed and expressed an interested in getting access to ort technology and establishing a collaboration
Collaborator Contribution We have discussed and applied a work program together over several months, and executed the appropriate legal agreements. The technical validation work is due to be initiated within Q1 2018
Impact Outputs are still pending.
Start Year 2017
 
Description BBSRC Enterprise Fellowships Networking Event 
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 BBSRC Enterprise Fellowships Networking Event
Year(s) Of Engagement Activity 2017
 
Description Croda Open Innovation Day 
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 New project ideas discussed.
Year(s) Of Engagement Activity 2017
 
Description EuroScience Open Forum (ESOF) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact EuroScience Open Forum (ESOF):

+provide an open forum for debate on science and technology and research policies in Europe
+strengthen the links between science and society
+contribute to the creation of an integrated space for science and technology in Europe, linking research organisations and policies at national and EU levels; strive for a greater role of the EU in research and
+influence science and technology policies.
Year(s) Of Engagement Activity 2016
URL http://manchester2016.esof.eu/en/
 
Description FLS Community Open Day 
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 Schools
Results and Impact An outreach stand about biotechnology for the production of fragrance compounds and public opinion of synthetic biology
Year(s) Of Engagement Activity 2016
 
Description Institute Open Day (Outreach) 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Synthetic Biology stand at MIB open-day attended by >200 A levels students
Year(s) Of Engagement Activity 2014,2015,2016
 
Description Institute Open Day (Outreach) 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Prepare promotional material in advance of the meeting, and hosted the interactive stand 1,5 days

tbc
Year(s) Of Engagement Activity 2014
 
Description Invited Speaker at European Congress on Biotechnology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Q&A

Lead to new contacts
Year(s) Of Engagement Activity 2014
 
Description Invited Speaker at the UK-South Korea Synthetic Biology Workshop. Heathrow UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Q&A

New potential collaborators in Korean
Year(s) Of Engagement Activity 2015
 
Description Invited speaker at ELRIG Advances in Protein Technology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Sparked Q&A immediately afterwards. Led to follow up discussions with three different researchers, two of which have led to ongoing collaborations

We have transferred the technology discussed in the talk into a new collaborators institute, who is a leading national service provider in the relevant field.
Year(s) Of Engagement Activity 2013
URL http://elrig.org/portfolio/advances-in-recombinant-protein-technology-2013/
 
Description Invited speaker at Society of General Microbiology AGM, 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Q&A

Follow up contact with members of the research community
Year(s) Of Engagement Activity 2014
 
Description Rainbow Seed Fund Catapult Investor Insight Event, Court of Justice, London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Presentation on emerging areas from the academic research base to investors and press
Year(s) Of Engagement Activity 2017
 
Description SEB Synthetic Biology Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Talk sparked questions and discussions. A number of new potential collaboration contacts were made.

Was asked to come for a Faculty visit at another institute
Year(s) Of Engagement Activity 2014
URL http://www.sebiology.org/meetings/Past_Meetings/synthetic_biology/overview.html
 
Description SMART-Map Industrial Dialogue on Synthetic Biology 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact Workshop on the responsible development of Synthetic Biology which forms part of the EU H2020 SMART-map project.
Year(s) Of Engagement Activity 2017
URL http://projectsmartmap.eu/
 
Description SynBioChem Workshop on Responsible Research and Innovation 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Study participants or study members
Results and Impact Roundtable discussant at SynBioChem Workshop on Responsible Research and Innovation
Year(s) Of Engagement Activity 2015
 
Description iGEM Giant Jamboree 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Synthetic Biology iGEM Giant Jamboree
Year(s) Of Engagement Activity 2016
URL http://2016.igem.org/Giant_Jamboree