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Engineering saponin biosynthesis pathways for bio-production of novel vaccine adjuants

Lead Research Organisation: John Innes Centre
Department Name: Biochemistry and Metabolism

Abstract

Plants are a rich source of drugs and other high-value compounds. During the nineteenth century, advances in chemistry enabled many bioactive natural products to be purified from plants and their structures determined, paving the way for the emergence of the pharmaceutical industry. The first naturally derived pure medicine to be commercialized was morphine, extracted from opium Merck in 1826. Subsequently efforts were made to make natural products by chemical synthesis, the first example being salicylic acid, produced commercially by Bayer in 1899. However, despite these and other successes, the vast majority of plant metabolic diversity has remained untapped due to the problems of accessing source species, purifying compounds and the challenges of chemical synthesis.

The ability to decode the chemical potential of plants by sequencing their transcriptomes and/or genomes and to then use this information as an instruction manual to make drugs and other high-value chemicals is opening up new routes to harness the vast chemical diversity of the Plant Kingdom. We have established transient plant expression technology for the rapid reconstruction of plant metabolic pathways and demonstrated that this system can be used to access gram-scale quantities of products. This technology is readily scalable and has been used for commercial production of vaccines. This project is intended to demonstrate that plant-based metabolic engineering is a viable route to the commercial production of pharmaceuticals (and other high-value compounds), and also a credible platform for the generation of molecular diversity and new product discovery. The focus of the proposed work is on engineering saponin biosynthesis pathways for bio-production of novel vaccine adjuvants. The outputs have the potential to broaden the diversity of available adjuvants and expand the resources and the capabilities of the vaccines industry as a whole, to the benefit of the industry and society.

Publications

10 25 50
 
Description Soapwort (Saponaria officinalis) is a flowering plant from the Caryophyllaceae family with a long history of human use as a traditional source of soap. Its detergent properties are because of the production of polar compounds (saponins), of which the oleanane-based triterpenoid saponins, saponariosides A and B, are the major components. Soapwort saponins have anticancer properties and are also of interest as endosomal
escape enhancers for targeted tumor therapies. Intriguingly, these saponins share common structural features with the vaccine adjuvant QS-21 and, thus, represent a potential alternative supply of saponin adjuvant precursors. We have sequenced the S. officinalis genome and, through genome mining and combinatorial expression, identified 14 enzymes that complete the biosynthetic pathway to saponarioside B. These enzymes include a noncanonical cytosolic GH1 (glycoside hydrolase family 1) transglycosidase required for the addition of d-quinovose. This work was published in Nature Chemical Biology in 2024 (Jo et al). We have also use combinatorial strategies to make suites of triterpene saponin analogues. Our results open avenues for accessing and engineering natural and new-to-nature pharmaceuticals, drug delivery agents and potential immunostimulants.
Exploitation Route This work has contributed to establishing the foundation of a new spin-out company from the Osbourn lab, HotHouse Therapereutics.
Sectors Chemicals

Healthcare

Manufacturing

including Industrial Biotechology

Pharmaceuticals and Medical Biotechnology

 
Description The focus of this project is on engineering saponin biosynthesis pathways for bio-production of novel vaccine adjuvants. This work has been instrumental in enabling the PI to establish a large new research programme on harnessing plant natural products as therapeutics, funded by a Wellcome Discovery Award (2024-2032). It has also paved the way for a new spin-out company, HotHouse Therapeutics, which became operational in July 2024 and has raised £3.7M in seed funds and grants.
First Year Of Impact 2024
Sector Chemicals,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Cultural

Societal

Economic

 
Description Attended Roundtable meeting to discuss how Government might further help in the UK's engineering biology sector.
Geographic Reach National 
Policy Influence Type Contribution to a national consultation/review
 
Description Member, UK Engineering Biology Steering Group (not the Engineering Biology Advisory Panel
Geographic Reach National 
Policy Influence Type Participation in a guidance/advisory committee
URL https://www.gov.uk/government/groups/engineering-biology-advisory-panel
 
Description Visit by Minister of State in the Department for Science, Innovation and Technology
Geographic Reach National 
Policy Influence Type Participation in a guidance/advisory committee
 
Description Harnessing plant metabolic diversity for human health
Amount £4,817,214 (GBP)
Funding ID 227375/Z/23/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2024 
End 12/2031
 
Description Drug delivery 
Organisation University of Fribourg
Country Switzerland 
Sector Academic/University 
PI Contribution We have initiated a collaboration to investigate the anti-cancer properties of plant medicinal compounds
Collaborator Contribution Collaborative work involving assays of purified compounds
Impact This is a multi-disciplinary collaboration involving plant metabolic biology and medicinal chemistry
Start Year 2024
 
Company Name HotHouse Therapeutics 
Description HotHouse Therapeutics develops natural biotechnology solutions. 
Year Established 2020 
Impact Company operational from July 2024, with a seed fund raise of ~£3.7 M
 
Description "A million shades of green: Harnessing plant metabolic diversity for therapeutic applications" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact SCI Engineering Biology Conference, theme of translation out of academia into industry.
Year(s) Of Engagement Activity 2024
 
Description "Unlocking a pharmaceutical treasure trove-Elucidation of the pathway for biosynthesis of saponariosides from the soapwort plant" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Post Doc talk at Plant Genomes, Systems Biology & Engineering Conference Nov. 29th - Dec. 2nd 2023, at Cold Spring Harbor Laboratory.
Year(s) Of Engagement Activity 2023
 
Description AO attended Synthetic Biology Industrial Translation Showcase @Synbio_Showcase:Synbite Showcase Programme at the Royal Academy of Engineering 17.11.22 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact The aim of the 1-Day SynbiTECH Showcase was to reflect important issues and changes in the field of synthetic biology/engineering biology. As with the previous SynbiTECH meetings, the focus was primarily be on the development of the U.K.'s industrial and commercial synthetic biology/engineering biology sector. Consequently, the programme did not only reflect industrial and company development, but, also, important associated matters including strategy and policy, finance, policy and biosecurity.
Year(s) Of Engagement Activity 2022
URL http://www.synbicite.com/news-events/2022/nov/17/synbicite-showcase-2022/
 
Description Anne Osbourn Novozymes Prize Symposium - 'A million shades of green: Understanding and harnessing plant metabolic diversity' 
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 This Novozymes Symposium was focused on cutting edge research in understanding and harnessing plant metabolic diversity. Plants are chemical engineers par excellence, collectively making a vast array of structurally diverse natural products. These molecules have important ecological functions in nature. They are also important to humans for food, health and other industrial applications. The rapidly growing body of available plant genome sequence data is leading to a marked acceleration in the discovery of new biosynthetic pathways and chemistries. The focus of the symposium was on plant natural products - biosynthesis, function, mechanisms of metabolic diversification, and metabolic engineering. It included exciting talks from 12 invited speakers - experts in computational biology, integrated 'omics, biochemistry, metabolic biology, plant diversity and evolution, a mix of early career group leaders and more established research scientists from Europe, Asia and North America. Participants had ample opportunity to enjoy good food and networking in the coffee breaks, at lunch and dinner, and during the poster sessions. Registration was free for all attendees. Two publications have been generated as an outcome of this symposium, one already published in PLOS Biology, and another under submission (a commissioned highlight review for EMBO J, written by a team of five postdoctoral researchers from the Osbourn lab).
Year(s) Of Engagement Activity 2024
URL https://www.tilmeld.dk/anneosbournnovozymesprizesymposium
 
Description Anne Osbourn meeting with George Freeman MP during visit to Norwich Research Park 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Anne Osbourn met George Freeman MP (Minister of State in the Department for Science, Innovation and Technology) as one of the NRP Entrepreneurial Researchers.
Professor Anne Osbourn, Founder of Hothouse Therapeutics, spoke about Unlocking Nature's Inaccessible Chemistry.
Year(s) Of Engagement Activity 2023
 
Description Article - Vaccine Adjuvant QS-21 Produced in Tobacco 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact GEN Article quoting AS-21 Work.
Year(s) Of Engagement Activity 2024
 
Description Article on Spin out - Hothouse Therapeutics 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Article published in Biosciencetoday - New spin-out at Norwich Research Park harnessing plant power for next generation drugs
Year(s) Of Engagement Activity 2024
URL https://www.biosciencetoday.co.uk/new-spin-out-at-norwich-research-park-harnessing-plant-power-for-n...
 
Description Biological Diversity Work Group Panel 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 UKRI/BBSRC Biological Diversity Working Group in person and on zoom held on 23rd November 2023. Included 5 minute presentation on perspectives on biological diversity (including own research and wider opportunities, trends and drivers relating to biological diversity)
Year(s) Of Engagement Activity 2023
 
Description Conference Participant SynBITECH: Company Reviews and Panel Discussion: Women in SynBio 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Conference Participant SynBITECH: Company Reviews and Panel Discussion: Women in SynBio, Panel discussions
Year(s) Of Engagement Activity 2023
 
Description Cracking Natures Code, Engineering Biology (House Magazine) 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Content in magazine following an interview, which is targeted at the Houses of Parliament. Article Title: "Cracking Natures Code"
Year(s) Of Engagement Activity 2024
 
Description Discussion with Counsellor Kay Mason Billig - Leader of Norfolk County Council 
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 Policymakers/politicians
Results and Impact Visit to discuss site development
Year(s) Of Engagement Activity 2024
 
Description GEN Article on Vaccine Adjuvant QS21 
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 See article
Year(s) Of Engagement Activity 2024
URL https://www.genengnews.com/topics/bioprocessing/vaccine-adjuvant-qs-21-produced-in-tobacco/
 
Description Hosted school visit to our institute 
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 We worked with the Country Trust to host a group of children from a local Primary school to visit the John Innes Centre to do some experiments in the training lab on natural products. The children were very excited to come into the lab and enjoyed wearing lab coats and goggles and using real science equipment. We had lots of PhD students help with the activity and the children liked chatting to them about what it's like to be a scientist.
Year(s) Of Engagement Activity 2024
 
Description Independent review of UKRI Roundtable discussion co-hosted by the Campaign for Science and Engineering & Sir David Grant 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Anne Osbourn was a member of an independent review of UKRI. Roundtable discussion. Co-hosted by the Campaign for Science and Engineering and Sir David Grant.
Year(s) Of Engagement Activity 2022
URL https://www.ukri.org/news/ukri-welcomes-independent-review-report/
 
Description Interview with The House Magazine 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Interviewed for The Hot House Magazine about work with HotHouse Therapeutics in an article about Engineering Biology.
Year(s) Of Engagement Activity 2024
URL https://library.myebook.com/thehouse/house-supplement-focus-on-dsit-house-1760/5275/#page/28
 
Description Magazine Interview 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Interview with Journalist writing a piece about the Department for science, innovation and technology's vision for engineering biology, for House Magazine. Focusing on the vision and the government's aspirations for the field. Particular interest in way work is becoming increasingly important to medicine.
Year(s) Of Engagement Activity 2024
 
Description Member of Group - UKRI BBSRC Biological Diversity Working Group Meeting 
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 Biological Diversity Working Group in person and on zoom held on 23rd November 2023. Included 5 minute presentation on perspectives on biological diversity (including own research and wider opportunities, trends and drivers relating to biological diversity)
Year(s) Of Engagement Activity 2023
 
Description New Phytologist Workshop: Introducing Transformative Plant Biotechnology Interview 
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 Gave an interview introducing transformative plant biotechnology. Recorded during the workshop at the National Museum of Scotland, Edinburgh in 2023. Published on YouTube in January 2024.
Year(s) Of Engagement Activity 2023,2024
URL https://www.youtube.com/watch?v=8XrjN3Ye1XA
 
Description News Article on QS-21 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact See article
Year(s) Of Engagement Activity 2024
URL https://www.telegraph.co.uk/global-health/science-and-disease/the-chilean-tree-that-could-cure-malar...
 
Description Norwich Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Norwich Science Festival; interacting with the general public, Making Molecules
Year(s) Of Engagement Activity 2024
 
Description Novozymes Prize Lecture - From plant defence to therapeutics: The metabolic poetry of science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact From plant defence to therapeutics: The metabolic poetry of science - Anne Osbourn presented the 2023 Novozymes Prize Lecture at John Innes Centre on Monday 12 June 2023
Year(s) Of Engagement Activity 2023
 
Description Oral Presentation - "Finding Drugs in the garden: Harnessing plant metabolic diversity for therapeutic applications" 
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 Oral presentation "Finding Drugs in the garden: Harnessing plant metabolic diversity for therapeutic applications" given at the New Phytologist Transformative Plant Biotechnology Workshop in Edinburgh on 20 September 2023.
Year(s) Of Engagement Activity 2023
 
Description Oral Presentation - "Harnessing plant metabolic diversity for food and health applications" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact High Value Biorenewables Annual Meeting, 14-15 November 2023 in Manchester. Oral Presentation - "Harnessing plant metabolic diversity for food and health applications"
Year(s) Of Engagement Activity 2023
 
Description Panel Member - UKRI Connect Transforming Tomorrow Together Event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Panel Member at UKRI Connect Transforming Tomorrow Together Event held on 20th October 2023. Aim of event was to showcase and discuss the local impacts of research and innovation, and how innovation in funding approaches can help facilitate this, consisted of two panels.
Year(s) Of Engagement Activity 2023
 
Description Presentation at Royal College of Physicians: "Finding drugs in the garden: harnessing plant metabolic diversity for therapeutic applications" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Gave a presentation to Royal College of Physicians at their Medicinal Plant Lectures: July 2024, RCP at Regent's Park, London UK
Year(s) Of Engagement Activity 2024
 
Description Presentation on HotHouse Therapeutics 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presented HotHouse Therapeutics at plenary event at the UKRI Connect Stakeholder engagement event.
Year(s) Of Engagement Activity 2023
 
Description School Visit (Cambourne) - SAW Trust 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact 2 day hands-on SAW workshop for year 6 children at a Primary school in Cambourne. Aim to inspire and inform school children - there were 4 science activity stations followed by a creative writing activity and art activity.
Year(s) Of Engagement Activity 2023
 
Description Sci Comm East Conference Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Ran a Science Art and Writing workshop at Sci Comm East Conference for people interested in creative approaches to public engagement. The participants worked through a plant natural product activity to learn how to use science topics to explore real research and then extend learning through creative writing and art.
Year(s) Of Engagement Activity 2024
 
Description Science Art and Writing Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact We visited a local Primary school to run a Science Art and Writing Project on the theme of natural products from plants. The children explored the diversity of natural products and had a go at extracting colour pigments from a variety of flowers and used acid/base reactions to identify chemicals. Then they learned about inflammation in our bodies and how some medicines have been developed to target this. We looked at boswellic acid which is extracted from frankincense trees and is a potent anti-inflammatory drug and passed around some frankincense for the children to feel and smell. The final experiment gave the children a mock ELISA assay plate and a selection of plant extract samples which they had to test for activity as anti-inflammatories. They further explored the concepts and new vocabulary though poetry writing and visual art activities.
Year(s) Of Engagement Activity 2024
 
Description Science Art and Writing Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact We visited a local Primary school to run a Science Art and Writing Project on the theme of natural products from plants. The children explored the diversity of natural products and had a go at extracting colour pigments from a variety of flowers and used acid/base reactions to identify chemicals. Then they learned about adjuvants and which plants provide sources of these. We looked at soapwort plants and the children had a go at making foam bubbles using plant extracts. Then we introduced the story of the soapbark tree, the importance of the adjuvant QS21 for better vaccines and how scientists are replicating this molecule to try and protect the trees. In the final activity the children worked in groups and used molymod to build a range of triterpenes. They further explored the concepts and new vocabulary though poetry writing and visual art activities.
Year(s) Of Engagement Activity 2024
 
Description Science Communication Lecture 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact Ran a science outreach workshop as part of the University of East Anglia's Science Communication module. Students were first encouraged to think about why sci comm is important and who the various audiences are. We worked through some example activities to show how complicated concepts can be broken down to make them accessible to a non-science audience and we also explored cross-disciplinary approaches to science outreach and the benefits seen by giving people different ways to explore science topics.
Year(s) Of Engagement Activity 2023
 
Description Science, Art and Poetry activity 
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 Delegates at the Anne Osbourn Novozymes Prize Symposium held at the John Innes Centre on Sep 9th and 10th 2024 participated in plant natural product-themed art and poetry activities run by the SAW Trust, during the refreshment and poster sessions. Colour pigments, ice cubes and diffusion were used to create flower-like patterns that were added to a display that grew over the course of the event and acrostic poems using key words related to the research topics were generated by people each adding a line. These were performed during the closing remarks of the event as a collaborative piece. The activities created an opportunity for delegates to work together, create and play which fostered an atmosphere for relaxed dialogue and a chance to consider novel approaches to science communication.
Year(s) Of Engagement Activity 2024
URL https://sawtrust.org/
 
Description Seminar - "Harnessing plant metabolic diversity for food and health applications" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Seminar given at VIB-UGent Center for Plant Systems Biology - Title: "Harnessing plant metabolic diversity for food and health applications" on 22nd February 2024 as part of a wider visit to the Center.
Year(s) Of Engagement Activity 2024
 
Description Seminar: "Finding drugs in the garden: Harnessing plant metabolic diversity" in the @IPS2ParisSaclay amphitheater on Tuesday 22nd November at 2 pm 
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 Professor Anne Osbourn gave a seminar about "Finding drugs in the garden: Harnessing plant metabolic diversity" in the @IPS2ParisSaclay amphitheater on Tuesday 22nd November at 2 pm
Year(s) Of Engagement Activity 2023
 
Description Transforming Tomorrow Together Event Panel 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 Attended UKRI Connect Transforming Tomorrow Together Event as a panel member.
Year(s) Of Engagement Activity 2023
 
Description Visit by Novo Nordisk 
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 Industry/Business
Results and Impact TBC
Year(s) Of Engagement Activity 2023