GlycoCell Engineering Biology Mission Hub: Transforming glycan biomanufacture for health
Lead Research Organisation:
University of Nottingham
Department Name: School of Life Sciences
Abstract
Glycans or sugars have a huge impact on biological processes in all domains of life. Most medically important drugs are glyco-modified and vaccines often target the sugars on the surface of disease-causing pathogens. Hence, glycans play a key role in both biology and biotechnology. Optimising the expression and addition of sugars to proteins through glycoengineering offers an important avenue to creating lower cost, more effective vaccines, developing better therapies and diagnostics, and generating tools to more efficiently study health and disease. Glycans are difficult to study and manufacture and are considered the 'dark matter of biology'. This requires a new approach, and the advancement of Engineering Biology through our GlycoCell consortium is both timely and appropriate.
GlycoCell builds on our glycotechnology and Engineering Biology expertise and previous successes with a vision to scale and deploy a 'GlycoForge' facility as a UK national asset. The GlycoForge combines high-throughput automation, elegant experiment design, and advanced mathematical methods to rapidly engineer cells to make new glycans. GlycoCell will develop and integrate cutting-edge technologies, train the current and next generations of researchers, attract industry, and drive value-adding translation with the wider research community.
GlycoCell's targets will include bacterial and viral vaccines, as well as therapeutic proteins for treatment of other diseases. Vaccines are the most effective way to prevent infections and proven to reduce antimicrobial usage. The most successful vaccines against bacteria are glycoconjugates (glycans linked to proteins), which provide robust, lasting immunity in all age groups. Current glycoconjugate vaccine manufacture is costly and precludes use in resource poor settings or in veterinary medicine.
We will efficiently produce novel vaccines. We will target the human pathogen Group A streptococci and animal pathogen Streptococcus uberis. We will test the limits of the GlycoForges with the efficient expression of 100 glycan variants of Streptococcus pneumoniae and a novel Coxiella vaccine that has an as yet unresolved glycan structure. We will undertake a simulated pandemic 'pressure test' to deliver a 100-day rapid epidemic response that will be important for UK preparedness. These vaccines will be produced in parallel in bespoke E. coli and Bacillus cells which have multiple advantages for vaccine development and manufacture.
For therapeutic proteins, the glycan structure can dictate pharmacokinetics, protein turnover, and function. Most therapeutic glycoproteins are manufactured in mammalian hosts to match human glycan structures. These are costly to culture, challenging healthcare budgets and limiting patient access to therapies. We will use the GlycoForge to further develop bacteria and yeast cells to produce human-relevant glycans as novel therapeutics. This will include engineering Saccharomyces yeast cells able to mimic the glycosylation patterns of fungal pathogens, producing novel anti-fungal drugs. Pichia yeast cells will be used to produce novel viral vaccines including HIV and papilloma virus. This work will be supported by a world-leading facilities for analysis of glycans.
Training and development of the current and next generations of researchers across the UK and beyond will be central to GlycoCell and will be deeply integrated into all activities. A training program in engineering biology led by both academics and industrial partners will occur over 5 years.
GlycoCell will be led by an experienced management team and will be steered by an International Advisory Group to secure our vision to produce novel glycan-based medicines and to guide succession planning.
GlycoCell builds on our glycotechnology and Engineering Biology expertise and previous successes with a vision to scale and deploy a 'GlycoForge' facility as a UK national asset. The GlycoForge combines high-throughput automation, elegant experiment design, and advanced mathematical methods to rapidly engineer cells to make new glycans. GlycoCell will develop and integrate cutting-edge technologies, train the current and next generations of researchers, attract industry, and drive value-adding translation with the wider research community.
GlycoCell's targets will include bacterial and viral vaccines, as well as therapeutic proteins for treatment of other diseases. Vaccines are the most effective way to prevent infections and proven to reduce antimicrobial usage. The most successful vaccines against bacteria are glycoconjugates (glycans linked to proteins), which provide robust, lasting immunity in all age groups. Current glycoconjugate vaccine manufacture is costly and precludes use in resource poor settings or in veterinary medicine.
We will efficiently produce novel vaccines. We will target the human pathogen Group A streptococci and animal pathogen Streptococcus uberis. We will test the limits of the GlycoForges with the efficient expression of 100 glycan variants of Streptococcus pneumoniae and a novel Coxiella vaccine that has an as yet unresolved glycan structure. We will undertake a simulated pandemic 'pressure test' to deliver a 100-day rapid epidemic response that will be important for UK preparedness. These vaccines will be produced in parallel in bespoke E. coli and Bacillus cells which have multiple advantages for vaccine development and manufacture.
For therapeutic proteins, the glycan structure can dictate pharmacokinetics, protein turnover, and function. Most therapeutic glycoproteins are manufactured in mammalian hosts to match human glycan structures. These are costly to culture, challenging healthcare budgets and limiting patient access to therapies. We will use the GlycoForge to further develop bacteria and yeast cells to produce human-relevant glycans as novel therapeutics. This will include engineering Saccharomyces yeast cells able to mimic the glycosylation patterns of fungal pathogens, producing novel anti-fungal drugs. Pichia yeast cells will be used to produce novel viral vaccines including HIV and papilloma virus. This work will be supported by a world-leading facilities for analysis of glycans.
Training and development of the current and next generations of researchers across the UK and beyond will be central to GlycoCell and will be deeply integrated into all activities. A training program in engineering biology led by both academics and industrial partners will occur over 5 years.
GlycoCell will be led by an experienced management team and will be steered by an International Advisory Group to secure our vision to produce novel glycan-based medicines and to guide succession planning.
Technical Summary
GlycoCell builds on our collective knowledge of glyco-engineering, synthetic biology, advanced analytics, yeast genomic engineering, and design of experiments (DoE). Following recent success applying synthetic biology to glycotechnology, we have an ambitious vision to build a GlycoForge facility as a UK national asset for the development of vaccines, diagnostics and therapeutics.
GlycoForge will increase the scale and capacity of our engineering biology approach using key automation and design principles to develop a pipeline allowing rapid generation of synthetic construct libraries, screening and refinement. The technology will be developed in phases, integrating DoE with the help of partner Synthace, and other glycoengineering tools developed during GlycoCell. Cross-cutting, multisite glycoanalytics capabilities will enable this work. GlycoForge will be used for objectives including (i) high-yield production of glycoconjugate vaccines for neglected Streptococcal diseases; (ii) ambitious production of 100+ S. pneumoniae serotypes in E. coli (iii) a vaccine against a previously intractable target (O-antigen from Coxiella), (v) pressure test the system in 100 days with a hypothetical outbreak.
New technologies will include a B. subtilis glycan production platform and improved variants of PglB, the key enzyme in protein glycan coupling technology. We will synthesise glycoprotein therapeutics in low cost production hosts, apply OSTs to enable production in E. coli, use cutting-edge genome engineering to humanise yeast strains for more efficient glycoprotein production, and engineer yeasts that mimic pathogen glycosylation for the production of fungal vaccines, a challenging but important target.
The hub will develop and integrate cutting-edge technologies, train the current and next generations of researchers and leaders, integrate with leading industry, and drive value-adding engagement with the wider research community and other stakeholders.
GlycoForge will increase the scale and capacity of our engineering biology approach using key automation and design principles to develop a pipeline allowing rapid generation of synthetic construct libraries, screening and refinement. The technology will be developed in phases, integrating DoE with the help of partner Synthace, and other glycoengineering tools developed during GlycoCell. Cross-cutting, multisite glycoanalytics capabilities will enable this work. GlycoForge will be used for objectives including (i) high-yield production of glycoconjugate vaccines for neglected Streptococcal diseases; (ii) ambitious production of 100+ S. pneumoniae serotypes in E. coli (iii) a vaccine against a previously intractable target (O-antigen from Coxiella), (v) pressure test the system in 100 days with a hypothetical outbreak.
New technologies will include a B. subtilis glycan production platform and improved variants of PglB, the key enzyme in protein glycan coupling technology. We will synthesise glycoprotein therapeutics in low cost production hosts, apply OSTs to enable production in E. coli, use cutting-edge genome engineering to humanise yeast strains for more efficient glycoprotein production, and engineer yeasts that mimic pathogen glycosylation for the production of fungal vaccines, a challenging but important target.
The hub will develop and integrate cutting-edge technologies, train the current and next generations of researchers and leaders, integrate with leading industry, and drive value-adding engagement with the wider research community and other stakeholders.
