Developing platforms for the production of diterpenoids

Lead Research Organisation: University of Cambridge
Department Name: Plant Sciences

Abstract

Plants produce a wide range of diterpenoids, many of which are used commercially such as a paclitaxel, employed in the treatment of cancers, and steviol glyclosides which are used as zero-calorie natural sweeteners. Many other useful diterpenoids cannot yet be commercially exploited due to their limited availability and/or high production costs. Using synthetic biology it is now possible to engineer organisms such as yeast so that they are able to convert simple sugars to high-value chemicals. This project will develop yeast, algae and higher plant species as "chassis organisms" which can be used for the scalable production of diterpenoids. Our project will focus in particular on compounds which could be used in the treatment of cancers, or used in skin products such as sunscreens to protect skin against harmful UV light. These biological production systems will also be useful in producing many other diterpenoids that are found in nature.

Technical Summary

The project will address issues of supply and high production costs of selected high value chemicals of particular interest to its industrial partners (GSK, Unilever and Croda) and will provide advances in technology for wider applications across UK research and industry.

Currently a number of plant diterpenoids are used in the pharmaceutical, agricultural, food additive and fragrance industries. These are sourced from a limited number of species, restricting their supply and greatly increasing their cost. Using synthetic biology and metabolic engineering, the project will develop new production systems for high value diterpenoids by exploiting recent gene-based discoveries and novel platforms developed by the academic partner laboratories.

The aim of this project is to develop scalable heterologous production systems for diterpenoids. First, "chassis organisms" will be constructed that can supply elevated levels of the common diterpenoid precursor geranylgeranyl pyrophosphate. Genes for secondary metabolism will then be introduced into these chassis to create strains producing specific target compounds. We will then scale up laboratory production processes to pilot scale (eg 100 litre fermenter) and develop processes for the purification of the target compounds. Although we will focus primarily on specific diterpenoids of interest to the industrial partners within our consortium, the GGPP producing chassis will be universal in that they could also be adapted to produce a wider range of diterpenoids of interest to the pharmaceutical, personal care, food, fragrance and agricultural industries.

The overall team has a very good balance of 'push and pull' and is well placed academically, technically and commercially to deliver a high impact project for the IB Catalyst.

Planned Impact

As described in proposal submitted to TSB

Publications

10 25 50
publication icon
Brodie J (2017) The Algal Revolution. in Trends in plant science

publication icon
Scaife MA (2015) Establishing Chlamydomonas reinhardtii as an industrial biotechnology host. in The Plant journal : for cell and molecular biology

publication icon
Scaife MA (2016) Towards developing algal synthetic biology. in Biochemical Society transactions

 
Description Industrial biotechnology uses biological systems to generate a range of products, from pharmaceuticals, food additives and colourants, vitamins, and other chemicals. It is an increasingly important sector because it offers the way to make these materials more efficiently and with less reliance on fossil fuels. In this project, which is joint between Universities of York, Cambridge and Reading, and three multinational companies, we are trying to establish a platform that will allow production of molecules called diterpenoids, which have potential as drugs. In Cambridge we are focussing on trying to get microalgae, simple aquatic plants, to make these compounds. We are about half way through the project and have already made a number of advances. We have established a tool-kit for manipulation of the microalgae that gives effective and reproducible expression of plant genes. And we have generated several strains that make the first diterpenoid compound we are interested in. We have also established a system to regulate expression of the genes in the microalga, which will be important if the compounds turn out to impede growth of the cells. This will allow us to have the genes switched off initially, and then only expressed once we have produced enough algal cells.
Exploitation Route Many of the tools that we are using will be made available to the academic community for research purposes.
Sectors Agriculture, Food and Drink,Chemicals,Pharmaceuticals and Medical Biotechnology

 
Description We have secured several additional grants to support work with companies or to develop open source tools
First Year Of Impact 2017
Sector Manufacturing, including Industrial Biotechology
Impact Types Policy & public services

 
Description BBSRC IBBE Strategy Panel
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact The Strategic panel provided advice and guidance for the setting up of the Networks in Industrial Biotechnology & Bioenergy (NIBBs), which aim to foster increased awareness and interaction between academics and industrialists in the bioeconomy. It was also important for the thinking behind the IB Catalysts, joint with Innovate UK & EPSRC. Many of the grants and proof-of-concept awards are aimed at increased sustainability through the use of IB solutions
URL http://www.bbsrc.ac.uk/funding/filter/networks-in-industrial-biotechnology/
 
Description Agri-Inno: Stimulating Innovation and Entrepreneurship in Egypt's Agricultural Sector
Amount £28,520 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2017 
End 01/2017
 
Description Growth optimisation in next generation algal bioreactors for bioactive compounds
Amount £10,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2018 
End 09/2018
 
Description Implementing Algebra guidelines to risk assessments of scale-up of non-native species
Amount £9,500 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 05/2017 
End 10/2017
 
Description Promoting algae for industrial biotechnology 
Organisation Rothamsted Research
Country United Kingdom 
Sector Academic/University 
PI Contribution I have been very active in promoting the idea of using algae as industrial biotechnology (IB) hosts. This has led to a successful BBSRC sLoLa award, and also contributed to the debate about how to cement the rather fragmented algal expertise in the UK. Ultimately the introduction of the BBSRC networks in IB (NIBBs) were borne out of this debate, and these include Phyconet, which is specifically algal biotechnology. In addition several other NIBBs consider using algae as source of novel products, pathways, genes (NPRONet, HVCfP), or as platforms for community based metabolism (ADNET)
Collaborator Contribution Research and development collaborations with colleagues in the algal biotechnology field, but also in metabolic engineering and SMEs in algal biotechnology
Impact sLoLa Several BBSRC NIBBs, with Phyconet as specific one on algal biotechnology IB Catalyst award
Start Year 2009
 
Description Promoting algae for industrial biotechnology 
Organisation University College London
Department Division of Biosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution I have been very active in promoting the idea of using algae as industrial biotechnology (IB) hosts. This has led to a successful BBSRC sLoLa award, and also contributed to the debate about how to cement the rather fragmented algal expertise in the UK. Ultimately the introduction of the BBSRC networks in IB (NIBBs) were borne out of this debate, and these include Phyconet, which is specifically algal biotechnology. In addition several other NIBBs consider using algae as source of novel products, pathways, genes (NPRONet, HVCfP), or as platforms for community based metabolism (ADNET)
Collaborator Contribution Research and development collaborations with colleagues in the algal biotechnology field, but also in metabolic engineering and SMEs in algal biotechnology
Impact sLoLa Several BBSRC NIBBs, with Phyconet as specific one on algal biotechnology IB Catalyst award
Start Year 2009
 
Description Promoting algae for industrial biotechnology 
Organisation University of Aberdeen
Country United Kingdom 
Sector Academic/University 
PI Contribution I have been very active in promoting the idea of using algae as industrial biotechnology (IB) hosts. This has led to a successful BBSRC sLoLa award, and also contributed to the debate about how to cement the rather fragmented algal expertise in the UK. Ultimately the introduction of the BBSRC networks in IB (NIBBs) were borne out of this debate, and these include Phyconet, which is specifically algal biotechnology. In addition several other NIBBs consider using algae as source of novel products, pathways, genes (NPRONet, HVCfP), or as platforms for community based metabolism (ADNET)
Collaborator Contribution Research and development collaborations with colleagues in the algal biotechnology field, but also in metabolic engineering and SMEs in algal biotechnology
Impact sLoLa Several BBSRC NIBBs, with Phyconet as specific one on algal biotechnology IB Catalyst award
Start Year 2009
 
Description AlgaeEurope 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Presentation of research into algal synthetic biology to the principle conference in Europe aimed at supporting and developing the algal biotechnology sector. About half the participants were from industry (including large multisector, SMEs and startups)and 10% or so policy makers and officials eg from EU. The aim was to inform this group about the potential of synthetic biology in developing algal industrial biotechnology, providing the impetus to consider algae as production platforms for high value products as well as simply for biomass production. As a result, a consortium has been formed of academic colleagues who will share best practice and resources in SynBio.

I also described our recently opened Algal Innovation Centre (AIC), where it is possible to carry out pilot-scale algal cultivation, including of GM algae. As a result of the talk several contacts have been made with companies who are interested in the AIC.
Year(s) Of Engagement Activity 2015
 
Description BBC Radio 4 Frontiers - What ever happened to biofuels? 
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 was one of 4 invited participants in this programme, broadcast on BBC Radio 4 and available as a podcast. I had many emails and contacts from the wider public, including at the Festival of Plants exhibit, generally indicating that this had increased people's awareness of the possibility to use solar energy with algae, not just for biofuels, but also for other 'green tech'. Their attitude to biofuels per se was also more positive.
Year(s) Of Engagement Activity 2013
URL http://www.bbc.co.uk/radio/player/b02ykygv
 
Description BBSRC funded Algal Biotechnology workshop for researchers and industry representatives from New Zealand and UK to discuss progress and opportunities in the exploitation of microalgae 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The workshop brought together algal researchers and industry representatives from New Zealand and UK to discuss progress and opportunities in the exploitation of microalgae, particularly as feedstock for aquaculture and as sustainable sources of novel bio-products. The UK delegation included six leading academics, together with representatives of four SMEs from the algal biotech sector: namely, Varicon Aqua, TeeGene Ltd, Greenskill Ltd and Algenuity. Approximate 20 NZ delegates joined the workshop and comprised algal researchers from the Cawthron Institute, several NZ universities, and biotech companies in the Nelson region. We were also honoured to be joined by Min Sung Park, a world authority on algal biotechnology and Distinguished Professor at the Centre for Microalgal Biotechnology and Biofuels, Institute of Hydrobiology, Wuhan, China
Year(s) Of Engagement Activity 2017
URL http://www.phyconet.org.uk/wp-content/uploads/2017/09/NZ-UK-workshop-report.pdf
 
Description High Value Products from Plants conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Presentation of algal synthetic biology approaches to help support algal industrial biotechnology. This was at a Network in Industrial Biotechnology & Bioenergy (NIBB) meeting organised by the High Value Compounds from Plants NIBB. Interest was sparked amongst researchers to consider using algae, as well as plants, and production platforms.
Year(s) Of Engagement Activity 2015
 
Description IntoBiology resource 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact A final year undergraduate student in Plant Sciences produced a webpage describing work on algae in Plant Sciences and Biochemistry. The webpage is part of the programme established by IntoBiology, aimed at encouraging school children to consider studying plant biology.
Year(s) Of Engagement Activity 2015
URL http://intobiology.org.uk/unlocking-the-potential-of-algae-how-the-green-stuff-in-your-pond-might-go...
 
Description PHYCONET (BBSRC NIBB) Meeting: "UK Microalgal biotechnology, creating a unified vision" Cambridge February 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact A workshop of academia, funders, policy makers and industry, aimed at identifying ways to augment and support the UK microalgal business. As a result of the meeting, we made links with several companies and have obtained two Business Interaction Vouchers
Year(s) Of Engagement Activity 2018
URL http://www.phyconet.org.uk/document_category/uk-microalgal-biotechnology-creating-a-unified-vision
 
Description Phyconet (BBSRC NIBB) Annual Meeting, Plenary speaker 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact The talk was aimed at showing that the potential exploitation of algae for industrial purposes needs to be underpinned by fundamental biological understanding. Several industrial colleagues agreed, saying they recognise the need for better algal taxonomy and physiology to support their activities and ensure their IP can be protected.
Year(s) Of Engagement Activity 2017
URL http://www.phyconet.org.uk/wp-content/uploads/2017/09/PAC17_programme.pdf
 
Description Pint of Science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact I presented a talk on the potential uses of algae for bioenergy production as part of the Pint of Science festival in Cambridge, where scientists engage with people having a drink in a local pub. This takes place in London, Cambridge, Bristol and other university towns each year. As result of my talk and questions afterwards, although most people were not aware initially what algae were, nor how they could be used to generate energy, their opinions became more positive and optimistic towards biofuels generally. Pint of Science was awarded "Points of Light" by the Prime Minister David Cameron in November 2015 and the founders were interviewed about it on London Live TV.
Year(s) Of Engagement Activity 2014,2015
URL https://en.wikipedia.org/wiki/Pint_of_Science
 
Description Science on Saturday, part of SET week in Cambridge 
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 We had a stand in the science tent outside Dept of Plant Sciences. We demonstrated what algae are, what we use for now and how they might be used in the future for energy production. There were activities such as viewing microalgae with microscopes, extracting different light-harvesting pigments, and observing algae phototaxis. Children could handcraft their own algae using pipe cleaners or take part in an interactive algae quiz to win prices.

School asked for visit to talk to years 10-13.

Established the material to mount a Royal Society Summer Science Exhibit
Year(s) Of Engagement Activity 2006,2007,2008,2015,2016
 
Description Science on Sundays 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Short talk and Q&A on the nature of algae and how their characteristics could be used for sustainable energy, water remediation, or other green tech solutions. Held in the Cambridge Botanic Garden, the audience were interested in plants, and so this was an opportunity to provide information on what algae are, and how they might be used in novel ways. The audience fed back that they felt much better informed.
Year(s) Of Engagement Activity 2015
URL http://www.botanic.cam.ac.uk/Botanic/NewsItem.aspx?p=27&ix=196
 
Description The Life Scientific on BBC Radio 4 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I was interviewed by Jim Al-Khalili about my scientific career and interest in algae and vitamins. The programme "The Life Scientific" was broadcast on BBC Radio 4 and was also available on BBC iPlayer and as a podcast. As a result I have had numerous contacts about possible scientific and industrial collaborations, as well as enquiries from the general public about the various topics.
Year(s) Of Engagement Activity 2017
URL http://www.bbc.co.uk/programmes/b08bzl8y