The Dodding (Biochemistry), Savery (Biochemistry), and Woolfson (Biochemistry and Chemistry) groups have teamed up with Birte Hoecker’s lab in Bayreuth, Germany to design peptides that smuggle functional cargoes into human cells.
They have used these designer cell-penetrating peptides to take control of a molecular motor and to ferry organelles from the middle to the periphery of the cells.
Their paper about this research was published in Nature Chemical Biology in July 2022.
De novo designed peptides for cellular delivery and subcellular localisation
Guto G. Rhys, Jessica A. Cross, William M. Dawson, Harry F. Thompson, Sooruban Shanmugaratnam, Nigel J. Savery, Mark P. Dodding, Birte Höcker & Derek N. Woolfson Nat Chem Biol (2022). https://doi.org/10.1038/s41589-022-01076-6
The Woolfson (Chemistry and Biochemistry) and Clayden (Chemistry) groups have teamed up to make a new protein-like structure previously thought impossible. The work is reported in an article published in the journal Nature.
Most proteins are built from two structural building blocks – the alpha helix and the beta strand. These can be combined in different ways to generate an amazing gallery of 3D shapes that give natural proteins their many functions. Other structural building blocks do exist, but they are rare and thought not to be overly important in protein structure or function. One of these is called the 310-helix.
Uninhibited by the natural precedent for using alpha helices and the beta strands, and working between the two labs, Dr Prasun Kumar designed a protein-like molecule made solely from 310-helices. To do this, Prasun combined amino acids – the chemical units of proteins – that are found in natural proteins with others that are not. He made these designer proteins by chemical synthesis and showed that they formed bundles of pure 310-helices using X-ray crystallography.
The team now plans to probe this so-called “dark matter” of protein structure to explore chemistries and functions that go beyond those of natural proteins.
The work is funded by the BBSRC, supported by BrisSynBio, and involved a collaboration with Dr Neil Paterson at the Diamond Light Source.
As part of City Nature Challenge 2022, a team of PhD candidates at the University of Bristol have led hands-on, family-friendly public engagement activities explaining how the cutting edge science of environmental DNA (eDNA) sequencing can be used to identify local wildlife. DNA sequencing has been taking place in universities and research labs for half a century, but the Bento Lab – a portable, hand-held DNA lab – is allowing citizen scientists to study the DNA of living things around them. The University of Bristol team used a series of escape room-like activities to bring to life the processes involved in using the Bento Lab.
The activities took place in Queen Square, Castle Park and Tyntesfield in Bristol, and were led by (l-r) Matt Tarnowski, Claire Noble, Hannah Langlands, Harry Thompson and Rosie Maddock.
An activity introducing the microscopic world of biology at our fingertips
DNA can be collected from inside an organism’s cells in a process that is a bit like popping a balloon. This was the first task to participants had to do – the balloon had been filled with the letters G, T, C, A to represent DNA – and they then extracted the ‘DNA’ using a pipette. As it is hard to study DNA from so few cells, a polymerase chain reaction (PCR) is used to amplify a particular DNA sequence within the cells. Attendees had to figure out how the PCR process works using coloured dominoes, and all succeeded in understanding that it involves repeatedly doubling the targeted DNA.
This amplified DNA can be selected using gel electrophoresis, which was demonstrated using a noisy rain-stick. The final step is sequencing the DNA, and participants enjoyed donning a cape to give them the ‘superpower’ of being able to read DNA. Since these lab tasks would take hours with the Bento Lab, environmental samples that were brought along were taken away for identification, and attendees will be notified of their species once analysed.
Interactive activities brought eDNA sampling, PCR, the Bento Lab & DNA sequencing to life (l-r)
Putting the mobile eDNA lab to the test
Some creatures, such as fungi or microorganisms, can be hard to spot, yet play essential roles in the environment. The next stop for the Bento Lab is to assess fungal diversity at a site of ecological restoration. The Refungium at Coed Talylan in Wales aims to foster the highest diversity of fungi in the UK. The Refungium will be a refuge for native mushrooms, and studying the fungi there with the Bento Lab will inform restoration of this 15-hectare semi-natural woodland.
Would you like to host the eDNA lab?
We welcome opportunities to share this portable workshop, be it at a school, college, university or festival. With activities for all ages, this citizen science experiment has the potential to inspire the next generation of bioscientists and stewards of the environment. As well as learning how eDNA studies work, it opens up conversations about genetics, synthetic biology, ecology, microbiology, sustainability, climate change and responsible research. These themes mesh with the sustainability and climate change strategy recently shared by the UK’s Department for Education. If you would like to host the eDNA lab, please write to us.
Matthew Tarnowski, Claire Noble, Hannah Langlands, Rosie Maddock and Harry Thompson developed this project, which was funded by the EPSRC/BBSRC Centre for Doctoral Training in Synthetic Biology (SynBio CDT) Outreach Award.
Imre Berger, Professor of Biochemistry and Chemistry, Co-Director of the Bristol BioDesign Institute, and Director of the Max Planck Bristol Centre for Minimal Biology, has been elected as a Fellow of the Academy of Medical Sciences for his outstanding contributions to biomedical science and notable discoveries during the COVID-19 pandemic.
This year, the Academy has elected 60 outstanding biomedical and health scientists to its Fellowship for their remarkable contributions to biomedical and health science and their ability to generate new knowledge and improve the health of people everywhere.
Professor Berger’s work includes a number of significant breakthroughs in the fight against COVID-19. His team discovered a druggable pocket in the SARS-CoV-2 Spike protein that could be used to stop the virus from infecting human cells, blocking transmission and forestalling severe COVID-19 disease. At the height of the pandemic, his team showed that exposing the SARS-CoV-2 coronavirus to a free fatty acid called linoleic acid locks the Spike protein into a closed, non-infective form inhibiting the virus’ ability to enter and multiply in cells, stopping it in its tracks.
The findings, published in Science, are now being used to develop new cost-effective treatments against all pathogenic coronavirus strains by Bristol-based Halo Therapeutics Ltd. The biotech company, co-founded by Professor Berger, is currently preparing for in-human clinical trials.
Other notable breakthroughs include the discovery that SARS-CoV-2-infected individuals could have several different SARS-CoV-2 variants hidden away from the immune system in different parts of the body, which may make complete clearance of the virus from infected persons, by their own antibodies, or by therapeutic antibody treatments, much more difficult.
Professor Berger is also pioneering new vaccine technologies. His team developed the ADDomer™, a thermostable vaccine platform for highly adaptable, easy-to-manufacture, rapid-response vaccines to combat present and future infectious diseases including COVID-19. A key benefit of the platform is the speed with which candidate vaccines can be identified and could be manufactured in large quantities without refrigeration, significantly facilitating distribution world-wide. Vaccine innovator start-up Imophoron Ltd, co-founded by Professor Berger, is bringing ADDomer™-based vaccines to the market.
Professor Imre Berger said: “I am honoured to have been elected to the Fellowship of the Academy of Medical Sciences.
“I am also deeply grateful for the great effort by the fantastic scientists, technicians, engineers and students in my team, past and present, and the collaborators whom I have the privilege to work with. As researchers, the pandemic has presented us with immense challenges which has only highlighted the importance of scientific endeavour and medical science. It is therefore rewarding to have had our contributions recognised by the Academy that also seeks to improve and support advances in this field.”
Professor Dame Anne Johnson FMedSci, President of the Academy of Medical Sciences said: “Each of the new Fellows has made important contributions to the health of our society. The diversity of biomedical and health expertise within our Fellowship is a formidable asset that in the past year has informed our work on critical issues such as tackling the COVID-19 pandemic, understanding the health impacts of climate change, addressing health inequalities, and making the case for funding science. The new Fellows of 2022 will be critical to helping us deliver our ambitious 10-year strategy that we will launch later this year.”
The new Fellows will be formally admitted to the Academy on Monday 27 June 2022.
Simeon Castle, SynBio CDT PhD Student. Photo by Felix Russel-Saw
A new centre for engineering biology will build on Bristol’s success in synthetic biology and accelerate translation of its pioneering research to address global challenges and boost the UK’s bioeconomy.
By applying engineering principles to living systems, engineering biology aims to solve some of the world’s most pressing challenges in health, food security, and the environment.
The Bristol Centre for Engineering Biology, BrisEngBio, brings together scientists from a wide range of disciplines – from biology and chemistry to data science and systems engineering. Partnering with deep tech incubator, Science Creates and Oracle for Research, the aim is to develop fundamental research discoveries into commercially viable applications that benefit people and the planet.
BrisEngBio is the evolution of the UKRI-funded Synthetic Biology Research Centre, BrisSynBio, which published more than 325 research papers, enabled the spin-out of eight biotech companies, and leveraged additional research funding of over £90M.
“BrisEngBio embodies the same spirit of discovery and entrepreneurship that made BrisSynBio one of the country’s most academically and commercially successful centres for synthetic biology. Through this, we have already demonstrated that our fundamental research discoveries can be made commercially relevant. Now, through BrisEngBio, we are putting the ecosystem in place to really accelerate both discovery science and its translation.
“BrisEngBio’s early-career researchers will be honorary members of Science Creates, and through this they will benefit from a bespoke training and mentoring programme in innovation and commercialisation,” said Professor Dek Woolfson, Principal Investigator and Director of BrisEngBio.
“It’s been fantastic to work with many of the spin-out companies that came from BrisSynBio through Science Creates, with Science Creates Ventures having led investment rounds totalling £7.5 million and directly invested in two of those companies Imophoron and Cytoseek. We look forward to building on those successes, continuing our partnership with the University, and enabling more of these important discoveries to be translated for global good,” said Dr Harry Destecroix from Science Creates.
BrisEngBio investigators Dr Thomas Gorochowski, Dr Lucia Marucci and Professor Dek Woolfson at the BrisEngBio launch event. Photo by Beeston Media
“Synthetic and engineering biology has enormous potential to address some of the major global challenges that we face today. For example, in healthcare, energy and food security. But this requires input from all areas of science. BrisEngBio is a truly multidisciplinary venture, involving 55 University of Bristol academics from 11 Schools across four Faculties, and three Research Institutes,” said Professor Woolfson.
Initial UKRI funding of £1.5M will support 12 research projects and early career researchers over two years. BrisEngBio will cross disciplines to develop truly novel research such as hijacking bacterial transport as an antimicrobial strategy; identifying novel natural products for drug discovery; and using machine learning to predict self-healing properties of biohybrid materials.
Aligned with the UK Government’s National Engineering Biology Programme (NEBP), the centre promises to strengthen the UK’s position as an international leader in biotechnology.
Co-Investigator Dr Thomas Gorochowski said: “BrisSynBio had unprecedented success in funding and nurturing the fundamental science behind synthetic biology. It is critical that centres like ours set the research agenda and help maintain the UK’s position at the forefront of synthetic biology. BrisEngBio will provide the ecosystem to drive translation of new discoveries into commercially viable and truly world-leading engineering biology.”
Collaborating with Oracle for Research, BrisEngBio will utilise advanced cloud computing to realise data-driven design that combines academic and industry expertise in data science, machine learning, and multi-scale modelling.
Alison Derbenwick Miller, Vice President, Oracle for Research, said: “We are delighted that Oracle Cloud technology can support next-generation discovery and innovation at the new Bristol Centre for Engineering Biology (BrisEngBio). Through our collaboration, Oracle for Research will continue to support University of Bristol projects that drive real change through discovery and accelerate important research.”
Co-Investigator Dr Lucia Marucci said: “This is such an exciting time to be working at the interface of the natural sciences and engineering. We have seen through the pandemic what impact synthetic biology can have on our ability to develop vaccines and treatments. At BrisEngBio, we will nurture early career researchers and help them transition their research from scientific discovery to solutions that are both commercially viable and have the potential to address some of our most pressing global challenges.”
Professor Wolfson said: “I am delighted and excited by the continued support from UKRI and Government for the important area of synthetic biology. The new centre will allow us to translate our discoveries in fundamental synthetic biology into cutting edge technologies with significant impact locally, nationally and internationally, and across healthcare, the bioeconomy and environment.”
PhD candidates Matthew Tarnowski and Harry Thompson are embarking on a short project attempting to develop a high sensitivity biosensor to identify individual species of bacteria in river water samples. This biosensor will be built using the SHERLOCK CRISPR-based technology, which has already been applied to a variety of tasks ranging from diagnosing ZIKA virus infection in patient samples to fish species identification. As avid wild swimmers, Harry and Matt are hopeful that this could be a useful tool in clarifying the safety of water to swim in. Ideally, the biosensor would enable the rapid identification of microbial species in rivers and other waterways used for swimming/recreation.
Matt said: “Water is like a glue that binds ecosystems: hydrating and connecting them through the microbial life it sustains. We seek to detect microorganisms which indicate healthy and unhealthy water.”
Harry added: “In our preliminary studies, we hope to generate initial results which show that the biosensor can reliably detect a single species in a mixture of microorganisms in the lab. We will also test samples from popular swimming and spring water locations and no doubt do a bit of wild swimming too.”
Biosensors can detect microorganisms in water that are invisible to the naked eye
The underpinning technological basis for this project is the SHERLOCK platform (specific high-sensitivity enzymatic reporter unlocking). This technology allows rapid (around 1h) and reliable detection of nucleic acids at concentrations as low as 1 molecule DNA per millilitre (zeptomolar).
This project involves a novel application of SHERLOCK: biosensing of microbes in water. The SHERLOCK technology has been previously demonstrated to work also as a lateral flow (LTF) based assay and developing the biosensor for LTF use would form the basis of any follow-on work.
Such a device could be used for simple, rapid assessment of swimming water by anyone, anywhere.
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”.
Imre Berger, Professor of Biochemistry and Chemistry, Co-Director of the Bristol BioDesign Institute, and Director of the Max Planck Bristol Centre for Minimal Biology, has been elected as a Fellow of the Academy of Medical Sciences for his outstanding contributions to biomedical science and notable discoveries during the COVID-19 pandemic.
