Representatives from the French Embassy visited University labs on 10 December to see some of the innovative COVID-19 research being undertaken at Bristol, including work on ADDomer™, a thermostable vaccine platform being developed by Bristol scientists to combat emerging infectious diseases.
Dr Rachel Millet and Arthur Belaud from the Embassy’s Innovation Branch, which seeks to drive France-UK business enterprise, met with scientists Professor Imre Berger and Frederic Garzoni, founders of Imophoron Ltd, the biotech start-up developing ADDomer that uses technology developed at an institution in France, and recently secured £4 million investment.
L to R: Arthur Belaud from the French Embassy, Dr Anne Westcott from the University, Dr Rachel Millet from the French Embassy and Professor Imre Berger at the University’s Max Planck Bristol Centre for Minimal Biology.
During the visit, the delegation took a tour of labs in the University’s Max Planck-Bristol Centre for Minimal Biology (MPBC), the GW4/Wellcome Trust Cryo-EM facility led by Prof Christiane Schaffitzel, and Science Creates, the Bristol-based incubator, which is operated in partnership with the University and supports scientists and engineers in commercialising ground-breaking innovations. Having recently opened its second facility in the city’s Old Market, the party met with Science Creates founder and Bristol graduate Dr Harry Destecroix to discuss the future of deep-tech eco-systems.
Professor Imre Berger, Director of Bristol’s Max Planck Centre for Minimal Biology, said: “We are honoured to host this visit from the French Embassy’s Innovation Branch to share knowledge and showcase the pioneering research that is being done in collaboration with our European colleagues and institutions.”
Press release issued: 10 December 2021 on University of Bristol News and Features~ article here.
CEO of Imophoron Ltd, Frederic Garzoni, and University of Bristol researchers, including Imophoron co-founder Professor Imre Berger, combine efforts to generate a promising vaccine candidate for COVID19.
Professor Imre Berger (left) and Frederic Garzoni (right) at the Life Sciences Building at the University of Bristol
Prior to the pandemic, Frederic Garzoni and Imre Berger bolstered their research in a synthetically engineered protein scaffold named ADDomer™, and with Oracle’s cloud computing technology and Cryo-Electron microscopy (Cryo-EM), the protein was found to be thermotolerant. Professor of Biochemistry, Christiane Berger-Schaffitzel, who was leading the Cryo-EM team, said that “seeing Fred’s vaccine design [at near atomic resolution] in such detail gave us confidence that we were on the right track”.
The protein’s novel ability to maintain its structural integrity without refrigeration, even for months on end, eliminates the cold chain problem that all other mRNA based vaccines are constricted to. To compare, COVID vaccines by AstraZeneca, Moderna and BioNTech need to be cooled at 4°, -20° or even -80°, which restricts their transportability to remote locations.
The protein contains a druggable ‘pocket’ in its surface, which can be injected with various live-attenuated diseases. Professor Imre Berger explains that the body then develops a strong immune response against the “small and harmless pieces of the virus on top of the surface of the ADDomer™”.
First tested on emerging infectious arbovirus, Chikungunya, the vaccine candidate can be used boost antibodies against a host of other viruses and diseases. Spurred on by the success of antibody development in animal models, the Cryo-EM work, accelerated by Oracle Cloud, was instrumental in fast-tracking the vaccine design with other viruses in its ‘pocket’. Today, Imophoron Ltd has secured a £4 million investment to accelerate three vaccines to clinical trials on humans; Chikungunya, RSV (respiratory syncytial virus), and COVID19.
When the first lockdown hit in 2020, a group of clinicians, virologists, chemists, biologists and other academics mobilised as the University COVID19 Emergency Research (UNCOVER) group to tackle the global health crisis. “Scientists everywhere mounted an unprecedented effort to decipher SARS-CoV-2 and the disease, in record time” says Adam Finn, UNCOVER lead and Bristol Professor of Paediatrics. UNCOVER labs urgently needed SARS-CoV-2 antigens to create tests to detect antibodies in the blood of people who had contracted the virus.
SARS-COV-2 virus image (left) and ADDomer™ COVID vaccine image (right)
Fred Garzoni volunteered to assist UNCOVER with supplying the reagents they needed, having worked closely with Bristol researchers Berger and Berger-Schaffitzel on ADDomer™. This was also a unique opportunity to test Imophoron’s protein scaffold technology and develop, as fast as possible, a thermotolerant COVID-19 vaccine candidate with the protein. Within weeks, a viable vaccine had been developed for use on animals in preclinical tests.
“We had access to everything and everybody through UNCOVER” said Fred Garzoni, who worked tirelessly with the Vet School and the ASU’s UNCOVER researchers including Mick Bailey, Jamie Mann, Joe Roe, and David Morgan. Their trials on animal models showed incredibly promising results. Not only did the COVID-19 vaccine candidate induce strong immune responses in subjects, but it critically interrupted virus transmissibility.
In addition, the vaccine may not need trained healthcare professionals to administer the dose. The vaccine was just as effective when administered intranasally as with a syringe, which would reduce the cost and complexity of rolling out worldwide pandemic vaccine programmes. In theory, you could self-administer the COVID vaccine as a nasal spray at home!
The distinctive features of this vaccine candidate – its thermostability and various methods it can be administered- truly set the ADDomer™ apart from existing vaccines. Now that the global uptake of the COVID vaccine stands at 47%, this discovery made by Imophoron Ltd and UNCOVER at the University of Bristol could truly transform the accessibility of vaccines to the most remote corners of the world.
In a recent policy paper, the UK Government have outlined an Innovation Strategy, which sets out their ambitions for an innovation-led economy. Zentraxa, an exciting spin-out of bioengineering researchers from the Bristol BioDesign Institute and the University of Bristol, have been featured in the document ‘UK Innovation Strategy: Leading the future by creating it’. This strategy focuses on how the government can support businesses innovate by making the most of the UK’s research, development and innovation system, to make the UK a global hub for innovation.
Zentraxa is manufacturing biopolymers for use in highly functional adhesives in medical and industrial settings and are establishing a new niche in the synthetic peptides market. They have been highlighted in the UK Innovation Strategy as an example of a highly-successful pioneer in this type of research. Co-founder and Director of Zentraxa, Paul Race, is a University of Bristol Professor of Biological Chemistry who set up the spin-out in 2017. From 2014-17 he served as Co-Director of the >£14M Bristol Centre for Synthetic Biology Research (BrisSynBio) and was a founding Director of the Bristol BioDesign Institute.
by Simeon Castle (PhD Student, University of Bristol)
Whether as a bioengineer you are designing proteins, bacteria, communities of cells, or even ecosystems, you are designing with a medium that undergoes genetic change, grows and multiplies, and is shaped by its environment. If you design with an inert media like steel or electronics, you end up with an static artefact (notwithstanding wear and tear). In contrast, bioengineering involves designing populations that will continue to change after design and manufacture. You’re designing future lineages. It is not enough simply to design phenotypes like colour or yield; you must also design evolutionary dispositions. How will your design continue to evolve? Will it lose designed functions or gain new ones? Can you slow its evolution? Can your designs adapt to future change? How do we design the evolutionary properties of organisms? Can we design biosystems to be predisposed to certain evolutionary outcomes? These are the questions we set out to answer in our new paper in Nature Communications (Castle et al., Nature Communications, 2021).
Designing the immediate traits of a biosystem without considering its evolutionary future can end in disaster. For example, killer bees were bred to increase yields of honey, yet this hyper-aggressive species has taken over much of America. Similarly, bacteria continually evolve resistance to our antibiotics in an arms-race we are losing. If this is what happens when past technologies have clashed with nature, what will evolution do with the next generation of biotechnologies? But evolution can also be a powerful design tool. We have applied evolutionary principles for millennia. Breeding has created the crops and livestock that we eat today. In the lab, directed evolution is used to optimise biological products like vaccines. We even use algorithms that mimic evolutionary principles to create art and engineering solutions that would be otherwise almost unimaginable. But using evolution as a design tool also depends on good evolutionary design. You must create biosystems capable of evolving the kinds of designs you want in a reasonable timeframe. It is no good using evolution to design a flying pig, if it would take millions of years for the pig to evolve wings.
In 1932, Sewall Wright introduced the concept of the fitness landscape. Ever since, it has aided scientists’ imaginations when thinking about evolution. In recent years, thanks to advances in DNA sequencing, it has been possible to measure parts of these landscapes in the lab. Our paper addresses how we might go beyond imagining or experimentally exploring these landscapes, and instead start sculpting them. We introduce the concept of the ‘evotype’, defined as the set of evolutionary properties of a designed biosystem. Like the genotype and the phenotype, the evotype is unique to the biosystem. It is determined through the interactions of the processes of genetic variation, the generation of function from sequence, and selection. The evotype can be thought of as an evolutionary landscape whose topology and navigability are determined by these processes.
Genetic variation is classically thought of as random. However, we discuss how the nature of mutation and recombination is itself partly determined by an organism’s genes. This means that some regions of the evolutionary landscape may be more accessible than others. Furthermore, the impact of genetic change on function is variable. Some mutations can have wild effects, and some might not change the function of the biosystem at all. You can think of this like altering a recipe for a cake: you might be able to swap raisins with dried apricots, and it won’t be that different. But even modest changes to the amount of salt in the recipe will dramatically change the flavour. Therefore, how designed function changes across sequence space is also a critical aspect of the evotype that must be considered.
Finally, engineered biosystems are unique in that they are a result of two selection pressures: natural selection and the goals of the engineer. Bioengineers need to consider how these design goals align with the survival pressures that the organism faces. If natural selection and the design goals are opposed, evolution will always eventually wreak havoc on a design. The interaction between natural and artificial selection is captured by a concept we introduce: ‘fitneity’. Fitneity is a function of both fitness (reproductive success), and its utility (success as a design), and it is this quality that bioengineers must strive to optimise.
We show how existing engineering principles and synthetic biology tools could be used to influence genetic variation, function, and fitneity, thus determining the evotype. In fact, many of the principles that make a system easier to engineer also make it more evolvable, hinting at a deep relationship between design and evolution. However, evolutionary landscapes are unimaginably vast and complex. So complex in fact, that they may never be fully understandable, let alone designable. As engineers we must approach biodesign with a sense of humility and acknowledge the risks, as well as the potential, of attempting to engineer evolution. As the chaos theorist Ian Malcolm from Jurassic Park puts it: “Evolution has taught us that life will not be contained. Life breaks free… it crashes through barriers dangerously… life finds a way”. Or, more simply, to quote the late evolutionary biologist Leslie Orgal: “evolution is cleverer than you are”.
A team of scientists from the University of Bristol, including BBI Director Professor Imre Berger, have formed a new biotech spin-out company ‘Halo Therapeutics Ltd’ that is developing potential treatments for coronavirus.
The scientists behind Halo Therapeutics were responsible for the breakthrough discovery of a molecule that changes the shape of the SARS-CoV-2 virus spike protein, which was published in Science. Professor Imre Berger, one of the team leading the drug’s development, explained: “The aim of our treatment is to significantly reduce the amount of virus that enters the body and to stop it from multiplying. Then, even if people are infected with the virus or exposed to it, they will not become ill because the antiviral prevents the virus from spreading to the lungs and beyond. Importantly, because the viral load will be so low it will likely also stop transmission.”
Halo Therapeutics Ltd is preparing for clinical trials. If proven to be effective, the antivirals could be used by people of all ages worldwide at the first sign of COVID-19 symptoms, or if they have been in contact with someone with the virus, preventing the virus from taking hold and stopping further transmission.
Studies show the treatments are potentially ‘pan-corona antivirals’ in that they will work against all coronavirus strains – including the highly contagious ‘UK (Kent)’, ‘South African’ and ‘Brazilian’ variants. Some examples of treatments that Halo are currently developing include a nasal spray and inhaler. The antiviral also has the potential to treat patients at all stages of covid-19 and to reduce transmissibility.
This webinar is a spotlight on plant synthetic biology, featuring three rising stars in one dynamic interactive session. Three early career researchers, hosted by Dr. Thomas Gorochowski and Dr. Emily Larson, discuss plant biology topics including reprogramming plant root growth, genome engineering, and the biodesign potential of marchantia polymorpha. The speakers include:
Dr. Jennifer Brophy (keynote) – ‘Reprogramming plant root growth using synthetic developmental regulation.’
Dr Quentin Dudley – ‘Genome engineering of Nicotiana benthamiana as an improved plant-based bioproduction system for medicinal alkaloids.’
Dr Eftychis Frangedakis – ‘Marchantia polymorpha: an emerging system for plant synthetic biology.’
You can watch the full recording, including Q&A here:
Coordinated by the University of Bristol, the ADDovenom Project engages in research on snakebite venom, from which thousands of people die each year. The University of Bristol, alongside the University of Liège, Aix-Marseille University, Liverpool School of Tropical Medicine and iBET, will use novel snakebite therapy to research antivenoms. Project Coordinator, Professor Christiane Berger-Schaffitzel, says –
“Our ultimate goal is to provide a low-cost, easy-to-produce, safe to administer, clinically effective and low dose type of antivenom that can be stored and used for community treatment ideally at the point-of-care – a substantial therapeutic advance to reduce the global mortality of venomous snake-bites.”
For updates on this interdisciplinary research venture take a look at the ADDovenom website, where you can find latest news items, research information, details on partners, and the experts behind the project.
~The ADDovenom team at the October 2020 kick-off meeting~
The Consortium will bring together leading virologists from ten research institutions including Drs Andrew Davidson and David Matthews from the University of Bristol. They will work alongside the COVID-19 Genomics UK (COG-UK) consortium, which plays a world-leading role in virus genome sequencing, and Public Health England to boost the UK’s capacity to study newly identified virus variants and rapidly inform government policy.
The consortium is led by Professor Wendy Barclay, from Imperial College London, who said: “The UK has been fantastic in sequencing viral genomes and identifying new variants – now we have to better understand which mutations affect the virus in a way that might affect our control strategies. We are already working to determine the effects of the recent virus variants identified in the UK and South Africa and what that means for the transmission of SARS-CoV-2 and vaccine effectiveness.”
Bristol will be leading on the application of synthetic biology approaches to engineer synthetic pesudovirus platform technologies to probe virus infectivity.
The Bristol BioDesign Institute‘s newly imagined webinar series for 2021 has been designed as a platform to invite the best international speakers that are aligned to our core areas of interest. These include; biomolecular design and assembly in the cell, development and delivery of bioactive molecules, minimal biology towards cell-like systems, advanced computing and digital biology. You can find our upcoming speakers for the year on the International Webinar Series section of our website.
The first speaker of 2021 is Professor Elisa Franco from UCLA, with BBI Directors, Thomas Gorochowski and Dek Woolfson, panelling. The seminar is followed by an audience Q&A session, and then a one-to-one interview where Dr. Gorochowski asks Professor Franco questions about how she got into synthetic biology and her predictions for its future.
You can watch Professor Franco’s seminar, on ‘Programming dynamic behaviors in molecular systems and materials‘ below, or on the BBI YouTube Channel.
Abstract – Biological cells adapt, replicate, and self-repair in ways that are unmatched by man-made devices. These processes are enabled by the interplay of receptors, gene networks, and self-assembling cytoskeletal scaffolds. Taking inspiration from this architecture, we follow a reductionist approach to build synthetic materials by interconnecting nucleic acid components with the capacity to sense, compute, and self-assemble. Nucleic acids are versatile molecules whose interactions and kinetic behaviors can be rationally designed from their sequence content; further, they are relevant in a number of native and engineered cellular pathways, as well as in biomedical and nanotechnology applications. I will illustrate our approach with two examples. The first is the construction of self-assembling DNA scaffolds that can be programmed to respond to environmental inputs and to canonical molecular signal generators such as pulse generators and oscillators. The second is the encapsulation of these dynamic scaffolds in droplets serving as a mimic of cellular compartments. I will stress how mathematical modeling and quantitative characterization can help identify design principles, guide experiments, and explain observed phenomena.
In a tribute to University of Bristol Professors Christiane Berger-Schaffitzel and Imre Berger‘s research, scientists use virtual reality to depict the novel pocket in the SARS-CoV-2 spike protein.
The discovery, in a group research paper led by Berger-Schaffitzel, finds that linoleic acid binds to a ‘druggable’ pocket in the spike protein’s protomers, which prevents the virus from attaching to human ACE2 receptors. The video visualises how a gating helix within one of the protomers opens to accommodate the linoleic acid in the pocket, as well as how Arginine 408 and Glutamine 409 interact with the linoleic acid, which acts like a ‘lid’ over the pocket to keep the molecule tightly bound.
