Ben Hardy, a Research Associate in the School of Biochemistry at the University of Bristol, won a prize for his poster at the Synthetic Biology UK conference (7-8 November 2022).
Summarising work from his PhD, Ben’s poster (Computational Design of a de novo Transmembrane Cytochrome) highlights the successful design of an artificial protein capable of electron transport within membranes – such a protein is an essential component for constructing novel bioenergetic complexes within cells.
This was Ben’s second poster success this year – he won first prize at the Advances in Protein Folding, Evolution & Design conference (April 2022) for the poster: ‘Computational design of Bioenergetic Membrane Proteins’ (pictured).
Red blood cells that have been grown in a laboratory have now been transfused into another person in a world first clinical trial led by a UK team including University of Bristol researchers.
This is the first time in the world that red blood cells that have been grown in a laboratory have been given to another person as part of a trial into blood transfusion.
If proved safe and effective, manufactured blood cells could in time revolutionise treatments for people with blood disorders such as sickle cell and rare blood types. It can be difficult to find enough well-matched donated blood for some people with these disorders.
The trial is studying the lifespan of the lab grown cells compared with infusions of standard red blood cells from the same donor. The lab-grown blood cells are all fresh, so the trial team expect them to perform better than a similar transfusion of standard donated red cells, which contains cells of varying ages.
Additionally, if manufactured cells last longer in the body, patients who regularly need blood may not need transfusions as often. That would reduce iron overload from frequent blood transfusions, which can lead to serious complications.
The trial is the first step towards making lab grown red blood cells available as a future clinical product. For the foreseeable future, manufactured cells could only be used for a very small number of patients with very complex transfusions needs. NHSBT continues to rely on the generosity of donors.
Two people have so far been transfused with the lab-grown red cells. They were closely monitored and no untoward side effects were reported. They are well and healthy. The identities of participants infused so far are not currently being released, to help keep the trial ‘blinded’.
The amount of lab grown cells being infused varies but is around 5-10mls – about one to two teaspoons.
Donors were recruited from NHSBT’s blood donor base. They donated blood to the trial and stem cells were separated out from their blood. These stem cells were then grown to produce red blood cells in a laboratory at NHS Blood and Transplant’s Advanced Therapies Unit in Bristol. The recipients of the blood were recruited from healthy members of the National Institute for Health and Care Research (NIHR) BioResource.
A minimum of ten participants will receive two mini transfusions at least four months apart, one of standard donated red cells and one of lab grown red cells, to find out if the young red blood cells made in the laboratory last longer than cells made in the body.
Further trials are needed before clinical use, but this research marks a significant step in using lab grown red blood cells to improve treatment for patients with rare blood types or people with complex transfusion needs.
Co-Chief Investigator Ashley Toye, Professor of Cell Biology at the University of Bristol and Director of the NIHR Blood and Transplant Unit in red cell products, said: “This challenging and exciting trial is a huge stepping stone for manufacturing blood from stem cells. This is the first-time lab grown blood from an allogeneic donor has been transfused and we are excited to see how well the cells perform at the end of the clinical trial.”
Co-Chief Investigator Cedric Ghevaert, Professor in Transfusion Medicine and Consultant Haematologist the University of Cambridge and NHS Blood and Transplant, said: “We hope our lab grown red blood cells will last longer than those that come from blood donors. If our trial, the first such in the world, is successful, it will mean that patients who currently require regular long-term blood transfusions will need fewer transfusions in future, helping transform their care.”
Dr Rebecca Cardigan, Head of Component Development NHS Blood and Transplant and Affiliated Lecturer at the University of Cambridge said: “It’s really fantastic that we are now able to grow enough red cells to medical grade to allow this trial to commence, we are really looking forward to seeing the results and whether they perform better than standard red cells.”
John James OBE, Chief Executive of the Sickle Cell Society, said: “This research offers real hope for those difficult to transfuse sickle cell patients who have developed antibodies against most donor blood types. However, we should remember that the NHS still needs 250 blood donations every day to treat people with sickle cell and the figure is rising. The need for normal blood donations to provide the vast majority of blood transfusions will remain. We strongly encourage people with African and Caribbean heritage to keep registering as blood donors and start giving blood regularly.”
Dr Farrukh Shah, Medical Director of Transfusion for NHS Blood and Transplant, said: “Patients who need regular or intermittent blood transfusions may result develop antibodies against minor blood groups which makes it harder to find donor blood which can be transfused without the risk of a potentially life-threatening reaction. This world leading research lays the groundwork for the manufacture of red blood cells that can safely be used to transfuse people with disorders like sickle cell. The need for normal blood donations to provide the vast majority of blood will remain. But the potential for this work to benefit hard to transfuse patients is very significant.”
A study led by the labs of Prof Steve Mann (Chemistry) and Prof Paul Martin (Biochemistry) at the University of Bristol has demonstrated a new potential anti-cancer therapy that boosts the body’s inflammatory response using miniature artificial particles called protocells. This discovery is documented in an article published in Advanced Science, which specialises in interdisciplinary studies.
Our inflammatory cells, macrophages and neutrophils in particular, have remarkable cancer surveillance capacities, and therefore they act as “vigilants” to detect any cancer cell arising in the body. However, when these immune cells encounter the malignant cells, rather than killing them, they generally feed them with nutrients, which favours cancer growth. In this study, we developed a novel therapeutic system to reprogram immune cells away from cancer nurturing and towards cancer killing.
To achieve this, we injected miniature artificial protocells into the bloodstream of zebrafish, which are translucent and thus allow us to live image protocell dynamics and cell-cell interactions in real time. We observed that protocells were selectively taken up by inflammatory cells which were then reprogrammed, by specific cargoes loaded in the protocells, to make them more effective at killing cancer. The “reprogramming” cargo packaged in protocells was a miR223 inhibitor, anti-miR223, which maintains a pro-inflammatory/anti-cancer state in inflammatory cells, otherwise repressed by the presence of endogenous miR223. We showed that protocell-mediated reprogramming of the immune response led to reduced cancer cell proliferation and melanoma shrinkage in zebrafish.
In collaboration with Prof Ash Toye’s lab (Biochemistry), we established an in vitro assay with human macrophages supplemented with protocells. Our results showed that the protocells were able to promote anti-cancer reprogramming in human macrophages, too, which suggests that this novel protocell system may be a promising cancer immunotherapy strategy against human melanomas, and possibly also for other cancers with a pro-inflammatory vulnerability.
The research is explained in this scribble video:
Having demonstrated the ability of protocells to deliver cargoes to tumour-associated leukocytes and enhance their anti-cancer capacities, the Mann and Martin groups now plan to expand the therapeutic application of the protocell system beyond cancer and test the feasibility of using protocells to modulate the inflammatory response to unresolved/chronic wounds in order to improve wound healing in these clinically relevant inflammatory conditions. This research is currently ongoing and is supported by funding from BrisEngBio.
Macrophage Reprogramming with Anti-miR223-Loaded Artificial Protocells Enhances In Vivo Cancer Therapeutic Potential
Paco López-Cuevas, Can Xu, Charlotte E. Severn, Tiah C. L. Oates, Stephen J. Cross, Ashley M. Toye, Stephen Mann, Paul Martin Adv. Sci. 2022, 2202717, https://doi.org/10.1002/advs.202202717
Zentraxa, founded on IP generated through BrisSynBio, specialises in the design, production and testing of novel biomaterials. It has received £320k funding for commercial concept development of both medical adhesives and personal care ingredients that could have use in medicine, for example, skin bonding and wound care, or in personal use, such as skin and hair products.
Glaia, which benefitted from BrisSynBio commercialisation funding and dedicated innovation support, has secured £1 million in new investment to develop its carbon-based technology, the ‘sugar dots’, which increases crop yields and reduces emissions from crops by 30% when applied to the plants.
The Universities of Bristol and Edinburgh are collaborating on the Enzymatic Photocatalysis project, which will be led by Prof Nigel Scrutton at University of Manchester. This project will “apply a cyclical design-build-evaluate-learn approach to discovering the generalisable principles of photo-biocatalysis.”
The Bristol team will design completely synthetic proteins that trap light and funnel this energy into new enzyme-like activities for generating molecules that are otherwise difficult to make synthetically or biochemically.
Overview
Two BBSRC-funded post-doctoral research associate positions are available immediately to work in Dek Woolfson’s Peptide Design and Assembly group in the Schools of Chemistry and Biochemistry at the University of Bristol. Experience in one or more of peptide chemistry, protein biochemistry, de novo peptide/protein design, and the structural characterization of peptides and proteins would be an advantage. However, such experience is not essential, as we are looking for enthusiastic and talented researchers in the chemical/biochemical sciences who are interested in pursuing careers in peptide/protein design and its application in chemical and synthetic biology.
Post 1: De novo protein design in cells
This three-year post is joint with Dr Mark Dodding’s group (Biochemistry, Bristol). It builds on recent work between the Woolfson and Dodding groups (Cross et al.Cell Chem Biol(2021) DOI: 10.1016/j.chembiol.2021.03.010; Rhys et al.Nature Chem Biol(2022) DOI: 10.1038/s41589-022-01076-6). The project aims to design motor proteins from the bottom up to operate in eukaryotic cells.
Environment The Woolfson lab has purposed-built office space for computational work and laboratories for peptide chemistry, protein biochemistry, biophysics, protein crystallization, and cell biology. In addition, through Chemistry, Biochemistry, and the Bristol BioDesign Institute, the group has walk-up access to mass spectrometry, light and electron microscopy, and other facilities. The current group comprises 16 people with a balance of PhD and post-doctoral researchers from diverse backgrounds from around the world, which fosters a supportive, inclusive, and cutting-edge approach to peptide-design research.
Anike Te, Chief Strategy Officer for international materials company Lucideon, has joined the Bristol BioDesign Institute as an Aegis Professor in Engineering Biology. This prestigious appointment strongly aligns with our vision to be leading innovators in biomolecular and biosystems design and their translation, and for Bristol to be an internationally recognised centre in engineering biology.
Anike has experience in identification and adoption of new technologies into industry in healthcare, energy, construction, aerospace and ceramics in an international context. She has recently focused on the potential of synthetic biology to unlock sustainable, next generation materials.
Anike has also accepted a position on the Scientific Advisory Board for our UKRI-funded Bristol Centre for Engineering Biology, BrisEngBio, which was established to accelerate the translation of discovery synthetic biology research to address global challenges and boost the UK’s bioeconomy.
Anike will work across our portfolio of synthetic and engineering biology projects, surfacing and supporting the translation of novel therapeutics, diagnostics and materials. She will advise on the growth of our industrial networks to include new industries and new geographical regions, and mentor our new entrepreneurs.
The Aegis Professorship scheme was set up by the Science Partnership Office at the University of Bristol. In the scheme, visiting professors, who are leaders in their professional field, bring their up-to-date experience of work into academia. Through guidance and mentorship they facilitate joint working between researchers and external organisations such as industry and government.
Carmen Galan, Professor of Organic and Biological Chemistry and BrisEngBio Co-Lead for Innovation and Partnerships, said: “Working with Anike is a clear statement of our intention to work with industry to accelerate the translation of discovery synthetic biology research for real world benefit. The networks and expertise that Lucideon unlock for us aligns closely with our newest Bristol BioDesign Insititute research theme in Engineering Living and Sustainable Composite Interfaces.”
Imre Berger, Professor of Biochemistry and BrisEngBio Co-Lead for Innovation and Partnerships added: “Anike’s extensive expertise in establishing and leading international industrial networks will be a vital asset to accelerate new and potentially highly valuable projects that could evolve into transformative spin-outs and impacts. Having an external senior industrialist dedicate time to translation of research technologies is extremely valuable and Anike will be a perfect fit for this.”
Commenting on her appointment, Anike said: “It is a great honour to join the University of Bristol as an Aegis Professor in Engineering Biology. It’s a great opportunity to bring together academia and industry in an innovative, collaborative approach.”
“Lucideon is becoming increasingly involved in synthetic and engineering biology. It’s a very exciting area of science, which touches on many industries and technologies, and creates solutions to real-world issues, both in the UK and internationally.”
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.
Ben Hardy, a Research Associate in the School of Biochemistry at the University of Bristol, won a prize for his poster at the Synthetic Biology UK conference (7-8 November 2022).
Zentraxa
