Non-Enzymatic Catalysis in the Microbial Cell Interior

Lead Research Organisation: University of Edinburgh
Department Name: Sch of Biological Sciences

Abstract

Reducing our society's reliance on non-renewable fossil fuels is arguably one of the most important challenges facing the modern chemical industry.

Traditionally, the fields of synthetic organic chemistry and metabolic engineering have represented two independent solutions to this challenge. Whereas synthetic organic chemists use largely non-biological reagents to manipulate small molecules in multi-step processes, metabolic engineers encode synthetic pathways within a sequence of DNA and overproduce target compounds via fermentation. However, despite the respective (and potentially complementary) benefits of these two approaches, metabolic engineering and synthetic organic chemistry have existed as largely separate disciplines for over a century.

This Fellowship will merge these two fields by developing non-biological reactions for use within metabolically engineered microbial cells. It will, uniquely, focus on exploring these reactions in the cell interior and within designer metabolic pathways. Reactions will be targeted to various compartments of the cell using a "click" reaction between the catalyst scaffold and a genetically-encoded unnatural amino acid. Ultimately, this will enable microbial cells to synthesise molecules that are not found in Nature and therefore cannot be genetically encoded.

In doing so, this will also answer fundamental questions in the field, namely:

(i) Can non-enzymatic catalysis be truly integrated within an engineered metabolic pathway?
(ii) Can interactions between chemical catalysts and biomolecules within the cell enhance catalysis in vivo?
(iii) If so, can the chemical environment of the cell interior support modes of catalysis that are currently not possible in organic solvent?

Overall, this approach represents a unique solution to the problem of renewable chemical manufacture and will dramatically increase the range of small molecules that can be produced from biological feedstocks using engineered microbial cells.

Planned Impact

This project will address the critical limitation of a purely synthetic biology approach to small molecules synthesis by enabling the simultaneous use of chemical and biological catalysts in living microbial cells. By integrating abiotic reactions into designer metabolic pathways, the MICRO-CAT project will dramatically increase the range of small molecules that can be accessed from renewable feedstocks via microbial fermentation. As such, the impact of this research will be far-reaching and widespread.

Economic Impact: By reducing the cost of medicines to patients, and by diminishing these drugs' reliance on the availability of fossil fuel resources, such treatments will be made available to more patients for longer. This creates immediate economic benefit to the UK via sustained employment and reduced healthcare needs, and will ultimately lead to economic impact in the longer term through increased public acceptance and sustained commercial activity. Continuing the UK's tradition as a leading investor in emerging science in this area will attract investment and employees on the international stage. This will be no more crucial than in the coming years, and will ensure the long-term global performance and overall economic competitiveness of the UK in the biotechnology era. Impact in this area will be realised through a series of lectures, communications with local devolved and national governments via learned societies and the establishment of a spin-out company focussed on the development of chemical methods to manipulate cellular bioprocesses.

Industrial Impact: The development of abiotic catalysts for use in metabolic pathway design will stimulate efforts to develop sustainable bio-processes to high-value chemicals and synthetic intermediates. This will be transformative across multiple industries that currently rely on energy- and resource-intensive multi-step organic synthesis - i.e. the fine chemical, pharmaceutical, agrochemical, fragrance, flavouring, cosmetics, polymer and industrial biotechnology sectors. The novelty of this approach will therefore provide underpinning knowledge in the chemical and biosciences with broad utility across academia and industry. The impact of this project will also extend to improving existing bioprocesses, in particular those where metabolites are extracted and further manipulated via chemical synthesis. This will provide a cost-saving benefit to both the company and the end-user. Industrial impact will be realised via interactions with IBioIC, SCI, Edinburgh Innovations and will be directly supported throughout the Fellowship by the School of Biological Science's Commercial Relations Manager and the Head of Chemical Biology at Ingenza.

Public and Social Impact: By establishing a novel approach to the bio-based manufacture of small molecules of broad industrial significance the MICRO-CAT project will have both short- and long-term impact in the public domain. In the short-term, pharmaceutical products could become less costly as a result of these bioprocesses. In the longer-term, this project will help diminish the environmental impact of the petrochemical industry by diminishing our reliance on non-renewable fossil fuels and championing the use of engineered cellular systems as viable replacements. This will impact the health of, and healthcare available to, future generations. This impact will be realised at a societal level through a concerted series of public engagement activities, focussed on providing evidence of how biotechnology can diminish the impact our society is having on our planet and how this can positively impact our everyday lives. This will also be realised through social and online media presences, podcasts and short TV productions, and public laboratory demonstrations. The educational impact of the MICRO-CAT project will be pronounced and realised through a series of research-led teaching endeavours at the University of Edinburgh and beyond.

Publications

10 25 50
publication icon
Trotter CL (2023) Engineering biology for sustainable 1,4-butanediol synthesis. in Trends in biotechnology

publication icon
Sadler JC (2021) Interfacing non-enzymatic catalysis with living microorganisms. in RSC chemical biology

publication icon
Era Y (2021) Micellar catalysis of the Suzuki Miyaura reaction using biogenic Pd nanoparticles from Desulfovibrio alaskensis. in Green chemistry : an international journal and green chemistry resource : GC

publication icon
Sadler JC (2021) Microbial synthesis of vanillin from waste poly(ethylene terephthalate). in Green chemistry : an international journal and green chemistry resource : GC

 
Description We have recently been able to confirm that we can engineer E. coli bacteria to import small molecules using a newly-discovered mechanism originally found in human cells. This finding is significant as it is much more simple than the methodology originally outlined in the fellowship application and will enable us to rapidly test the main hypotheses of the fellowship's aims in 2022. We are currently building our first biosynthetic pathway to test our hypothesis.
Exploitation Route This could form the basis of general strategy for the use of chemical catalysts in metabolically engineered cells and enable the bio production of new chemical products from sustainable resources by fermentation. This hypothesis will be tested in 2022.
Sectors Chemicals,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description Elected to the Chemistry-Biology Interface Division Council of the Royal Society of Chemistry
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
URL https://www.rsc.org/membership-and-community/connect-with-others/through-interests/divisions/chemist...
 
Description Invited ECR to Senior Management UoE COVID Response Board
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
URL https://blogs.ed.ac.uk/iad4researchers/2020/09/23/inside-art-early-career-researcher-views-of-adapta...
 
Description Chemo-Enzymatic Modification of Microalgae Products 
Organisation MiAlgae
Country United Kingdom 
Sector Private 
PI Contribution After my FLF was announced, I was contacted by scientists at Mialgae as they were interested in using chemo-enzymatic methods to modify some of the products that they currently produce from microalgae. My team and I worked with them to write a proposal for a PhD studentship application, which was successfully funded in 2020 (£102,000)
Collaborator Contribution The partners have offered my team access to all their microalgae strains, to consult free of charge with us for the next 4 years and to host a member of my team for an industrial placement at their company for 3 months.
Impact A fully funded PhD application (IBioIC-CASE) in 2020 (£102,000)
Start Year 2020
 
Description Combined Non-Enzymatic Catalysis for the Valorisation of Sewage Waste 
Organisation Argent Energy
Country United Kingdom 
Sector Private 
PI Contribution After announcement of my FLF, Argent Energy contacted me as they were interested in supporting my combined synthetic chemistry and synthetic biology approach to help valorise oleic acid in fatberg waste into value added chemicals. We have since applied for an IBioIC-BBSRC PhD studentship on this topic, which was awarded in February 2021. My team and I have used the concepts outlined in my FLF proposal to propose a pathway in E. coli to make perfume compounds from fatberg waste provided by Argent and work on this is due to start in October this year.
Collaborator Contribution Argent have provided direct financial support for the project, will provide 'real' industrial waste samples when appropriate and will also host a member of my team at their site for a placement when appropriate.
Impact IBioIC-BBSRC PhD studentship (£103,815). The project is highly multidisciplinary and will involve chemists and biologists in my FLF team, as well as industrial chemists and engineers from Argent.
Start Year 2020
 
Description NCIMB Culture Screening 
Organisation NCIMB
Country United Kingdom 
Sector Private 
PI Contribution After the award of my FLF, NCIMB contacted me about collaborating to assess the inherent chemical potential of their vast culture collection of unsequenced microorganisms. Determining the chemical reactions that are possible using this resource will be an incredibly helpful to my FLF by creating new tools that can be used in the "enzymatic" sections of our chemo-enzymatic pathways. My FLF team and I have since worked with strain curators at NCIMB to identify 78 strains from their collection that are appropriate to screen for use in my fellowship.
Collaborator Contribution NCIMB scientists have worked with my team to triage their ca 10,000 strains and have identified relevant strains for our projects. To support our collaboration, NCIMB have also provided a significant discount to us, equating to £10,713.
Impact Our collaboration has recently been awarded a Business Interaction Voucher from the High Value Biorenewables BBSRC NIBB of £9,925, and the collaboration formally started in Feb 2021.
Start Year 2021
 
Description 27th Annual SCI Review Meeting on Hot Topics in Organic Chemistry (invited talk) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited to present a UK lecture on biotechnology at the SCI to academics and representatives from the UK chemical industry as part of their annual review meeting - selected from all ECR academics in biotechnology in the UK.
Year(s) Of Engagement Activity 2021
 
Description Advisory Panel Member for 'Engineering Biology', High Value Biorenewables BBSRC-NIBB 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Served on the advisory board for the Engineering Biology conference in 2021 where I advised on session topics, invited speakers and future NIBB activities.
Year(s) Of Engagement Activity 2021
 
Description Chemical, Structural and Synthetic Biology (CSSB) Cluster, Department of Chemistry, University of Warwick (invited seminar) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Chemical, Structural and Synthetic Biology (CSSB) Cluster, Department of Chemistry, University of Warwick (invited seminar)

Presented our work to the chemistry and biology departments at Warwick University and met with academic members of staff throughout the day.
Year(s) Of Engagement Activity 2022
 
Description Chemistry World Commentary 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited commentary on new industrial bioprocess by RSC Chemistry World
Year(s) Of Engagement Activity 2022
URL https://www.chemistryworld.com/news/reprogrammed-bacterium-turns-carbon-dioxide-into-chemicals-on-in...
 
Description Chemistry for Medicines Symposium Series, University College London (invited seminar) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Invited seminar to chemistry researchers from universities across London.
Year(s) Of Engagement Activity 2021
 
Description ClimateHub Innovators Panel Member, COP26 
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 Was invited to sit on the selection panel for the New York Times Innovators panel at COP26, selecting proposals from small start-up innovation companies in biotechnology to be showcased at COP26 in glasgow. Myself and a PDRA from the lab also attended COP26 as a result of this activity.
Year(s) Of Engagement Activity 2021
 
Description EXPLORE: Science for Sustainability, Edinburgh Innovations (invited seminar) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Recorded a podcast with one of our industry collaborators, NCIMB, about our work for Edinburgh Innovations. The event was also attended by industry representatives from around the UK.
Year(s) Of Engagement Activity 2021
 
Description Galileo, Germany, short film (South&Browse Media) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact participated in a short documentary on microbial biotechnology for a german TV channel. Filmed in Edinburgh in Dec '21.
Year(s) Of Engagement Activity 2022
 
Description Global consultant in biotechnology - Lululemon Athletica 
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 I was invited to serve as a global consultant in chemical biotechnology for the global sportswear company Lululemon Athletica. This was offered in recognition of our work over the past 3 years in this area, including research made possible through my FLF.
Year(s) Of Engagement Activity 2021,2022
 
Description Grant Review Panel Member, Flanders Research Foundation (FWO), Belgium 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Panel member for the FWO Circular Economy calls for research proposals. Invited to this role in 2021 and serving again in 2022.
Year(s) Of Engagement Activity 2021,2022
 
Description HVB Invited Talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact I was selected to present a talk on my research, entitled "Chemical and Enzymatic Catalysis in Microbial Cells for the Sustainable Production of Valuable Small Molecules" at the annual conference of the High Value Biorenewables NIBB (BBSRC).
Year(s) Of Engagement Activity 2020
 
Description Invited Keynote 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited keynote lecture at the International Symposium on Recent Trends in Chemistry, run virtually by the Institute of Chemistry at the University of Sargodha, Pakistan.
Year(s) Of Engagement Activity 2020,2021
 
Description Invited Seminar at Kings College London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact After the FLF was announced, I was invited to virtually visit the Department of Chemistry at Kings College London to give a seminar on my research.
Year(s) Of Engagement Activity 2020
 
Description KTN Accelerating Net Zero Chemical Manufacturing 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact I was invited to present my FLF approach as a member of a panel of experts in industrial biotechnology at an event run by KTN with the aim of presenting the benefits of biotechnology as an approach to reaching the UK's net-zero ambitions. My talk was titled "The Bipartisan Future of Industrial Biotechnology" and I was the only academic invited to present at this.
Year(s) Of Engagement Activity 2020
URL https://vimeo.com/470557388
 
Description Microbiology Society, online article 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact online article on the use of micro-organisms for green chemical synthesis
Year(s) Of Engagement Activity 2021
URL https://microbiologysociety.org/our-work/75th-anniversary-a-sustainable-future/circular-economy/circ...
 
Description SNaPNet Committee Member 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Due to the topic of my FLF research, I was invited to represent 'Biotechnology in Scotland' as a founding member of a new scientific network being launched in 2021. SNaPNet (Scottish Natural Products Network) aims to connect scientists from across academic fields and with industry to foster new collaborations in the field of natural products, their discovery and bio production using industrial biotechnology. I co-organised the launch event for this in Feb 2021 and will lead the organisation of a workshop in Q4 2021 focussed on 'synthetic biology approaches to non-natural products' to align directly with my FLF. The network is run in collaboration between SULSA, ScotCHEM, IBioIC and KTN.
Year(s) Of Engagement Activity 2021
URL https://www.bioeconomybuilder.com/events/snapnet
 
Description STEM Village Poster Presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I presented a virtual poster on my FLF at the STEM Village conference, which aims to promote the research being conducted by LGBTQ+ scientists in the UK.
Year(s) Of Engagement Activity 2020
 
Description SULSA-Zero Waste Scotland Sustainability Webinar for COP26 (invited seminar) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited to give a keynote lecture for SULSA in the lead up to COP26, where I was asked to showcase the research going on in our lab and in the wider biotechnology community in Edinburgh.
Year(s) Of Engagement Activity 2021
 
Description ScotChem Invited Seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact I was invited to present my research as part of the ScotChem ECR Seminar series to members of chemistry departments throughout Scotland. This included a 15 minute section on "my application to the Future Leaders Fellowship" where I was asked to promote the scheme and advise other ECRs who were thinking of applying.
Year(s) Of Engagement Activity 2020
 
Description Society for Applied Microbiology magazine article 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited magazine article on our recent collaboration with NCIMB, published online by SfAM.
Year(s) Of Engagement Activity 2021
URL https://issuu.com/societyforappliedmicrobiology/docs/sfam_microbiologist_december_2021_singles_med_r...
 
Description Strategic Advisory Board Member, Sustainable Chemicals Innovations Enabling Net Carbon Emissions (SCIENCE) prosperity partnerships (Nottingham-Warwick-Lubrizol) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Invited to sit on the advisory board for a new prosperity partnership in sustainable chemistry between Nottingham, Warwick and Lubrizol. WE meet twice per year to advise on the programme's directions and priorities.
Year(s) Of Engagement Activity 2021,2022
 
Description Sustainability Webinar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Was invited to lead a 'Science for Sustainability' webinar run by Edinburgh Innovations with the aims of outlining the benefits of biotechnology for the production of industrial chemicals.
Year(s) Of Engagement Activity 2020
URL https://twitter.com/EdinInnovations/status/1331560846930153475
 
Description Synthetic Biology and Biotechnology (SBB) conference (keynote) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Keynote lecture at SBB 2021
Year(s) Of Engagement Activity 2021
 
Description TEDx Talk - Vienna 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact TEDx invited me to present in Vienna alongside three other scientists. The talk was recorded and will be published on Youtube in Q1 2023.

Interview on talk: https://magazine.tedxvienna.at/2023/01/27/how-letting-bacteria-work-for-us-could-revolutionize-our-economy-an-interview-with-stephen-wallace-at-tedxvienna-on-the-rise/

Published Highlights: https://www.youtube.com/watch?v=1Kpcblh1M_A
Year(s) Of Engagement Activity 2022
URL https://magazine.tedxvienna.at/2022/09/15/tedxvienna-2022-speaker-line-up-on-the-rise-part-3/
 
Description Talk to ECRs at the University of Strathclyde 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact I was invited to present a talk on my engagement with industry and my FLF to ECRs at the University of Strathclyde.
Year(s) Of Engagement Activity 2020
 
Description Times Radio, interview on microbial biotechnology 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Tomes Radio interview on our work in microbial biotechnology
Year(s) Of Engagement Activity 2021
 
Description UK Government Scotland Research Highlight 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I recorded a short film on my FLF research to be published online as a Research Highlight by the UK Government Scotland. This was published online last year and has resulted in many follow-on emails from potential collaborators and increased visibility in my field.
Year(s) Of Engagement Activity 2020
URL https://twitter.com/UKGovScotland/status/1214501936587689984