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.
Since the start of lockdown 1.0 in March 2020, the BBI has been hosting a series of virtual seminars. Speakers have included Professors Anne Osbourn, Christine Orengo, Andreas Plueckthun, and many others. Lockdown has allowed us to broaden our speaker base on an international level, with academics from the US, Israel and Switzerland.
On 11 November, we had Professor Domitilla Del Vecchio from the Massachusetts Institute of Technology (MIT) give a webinar on ‘Context dependence of biological circuits: Predictive models and engineering solutions’. Panellists for the event were some of our own University of Bristol academics Dr. Thomas Gorochowski and Prof. Claire Grierson.
You can watch the full recording of the webinar here:
On the 31st October 2019, the Transforming UK Translation conference was held, bringing together Universities and Research Institutes to exchange ideas on bridging industry with academia. Hosted by the Royal Society, the Academy of Medical Sciences, the Royal Academy of Engineering and the Wellcome Trust, this one-off event was designed to address eight commitments in the Transforming UK Translation 10-year plan. Commitments from the hosts include opening training and development opportunities, fostering a system that rewards translation as part of research excellence, and that all work produced will have wider societal benefits.
Dek Woolfson
There were over 200 people in attendance, including our Royal Society Entrepreneur in Residence, David Tew, and BBI Director Prof Dek Woolfson. Meetings throughout the day consisted of talks, workshops and round table discussions with key stakeholders to address industry-academia engagements, their mutually beneficial partnerships and how to attract and train the right talent to drive these engagements.
A well-oiled machine: Lessons from Cambridge
An instance of successful translation is The Cambridge Department of Computer Science and Technology. In 20 years, they have founded over 270 companies. More than half of these are still active in 2020 with combined revenues of $1 billion and upwards. Their translational strategy is successful for several reasons:
Staff are encouraged by the department to be both entrepreneurs and academics simultaneously, which creates spin-outs and attracts business-minded researchers to the University in a continuous loop.
All negotiations regarding Intellectual Property are dealt with outside of the University to maintain positive relationships between entrepreneurs and businesses.
Entrepreneurial staff are encouraged and willing to mentor other industry hopefuls to create a supportive working environment. Friendly competition is welcomed with annual prizes given out.
Academics have space to develop companies more and publish a little less.
The department launches as many prospective businesses as possible rather than being selective. They aim to reduce negotiation time between all parties to help drive the quantity of start-ups.
The ‘golden share’ method is utilised when negotiating start-up contracts, where the University owns 2-3% of a company, but has control of at least 51% of the voting rights. This model is far easy to negotiate, is quicker to sort contracts and doesn’t dilute the University’s stake in the business.
For companies relatively new to the start-up businesses, like Bristol, there are a lot of lessons we can learn from this model. Having only started our first BrisSynBio spin-out in 2017, Bristol University is in its early stages of transforming translation.
BrisSynBio: The new kids on the block
At the conference, BrisSynBio at the University of Bristol was used as a successful example of thriving industry-academia collaboration. BrisSynBio is one of only six Synthetic Biology Research Centres in the UK, funded by BBSRC and EPSRC. BrisSynBio’s research focuses on aspects of biomolecular design and engineering and applying these in the field of synthetic biology. An Innovation Manager post was created to translate novel areas of synthetic biology research into real-life application. There are four UoB spin-out companies; Cytoseek, Imophoron Ltd, Rosa biotech and Zentraxa, specialising in synthetic biology research, including cell therapies, new vaccine candidates, biosensing technology and bioengineering pharmaceuticals respectively. Their combined successes have led to millions of pounds of translational funding from angel investors and venture capitalists, overseen by Dr David Tew.
Lessons from Transforming UK Translation:
How to attract, train and retain the right talent was an important take-away message from the conference. Currently, collaborations rely heavily on personal networking to enable industry-academia interactions. There is a need to hire full-time ‘connectors’ to create an obvious digital ‘gateway’ that either party can contact. Also, encouraging the mobility of people between academia, start-up companies, industry and incubators will benefit the innovative ecosystem function with less conflict and more healthy competition. To incentivise academics to innovate, Universities need to recognise knowledge share and transfer of technology as a positive output.
As well as negotiating intellectual property of academics, cultivating long-term, trusting relationships is of equal importance. The amount of student industrial placements, sponsored PhDs and apprenticeships should be increased to build healthy business partnerships. A thriving knowledge economy should be the goal of businesses and academics, and all parties should encourage the sharing and application of ideas beyond the academic setting wherever possible.
Finally, it’s important not to consider translation as commercialisation alone. Translation does not revolve only around the spinout of companies through innovative ideas- long-term professional partnerships are just as significant. We should propel the collaborations between technology-driven companies and academic institutions, using the innovative ability of the former and the research of the latter in a way that both sides may sustainably benefit.
Written by SynBio CDT students Claire Noble and Harry Thompson.
Do we have any chance of designing new ribosomes from scratch? Maybe not just yet, but that doesn’t mean Jon Bath, from the University of Oxford, isn’t getting started. While DNA origami hasn’t always been as glamorous as the world of protein design, that doesn’t mean there isn’t lots of exciting potential for new, DNA-based biomachinery.
The relatively simple nature of DNA folding based on base pairing has allowed for the construction of intricate and beautiful DNA structures. However, the field of designing DNA structure towards novel functionality is still being explored. In the past, DNA has been shown to be capable of moving along short tracks and assembling simple polymers in a directed way. Jon Bath is seeking to gain a deeper fundamental understanding of what dictates higher level folding in DNA origami, so that more complex designs can be attempted. He is making use of comparatively ‘simple’ DNA structures, with uncommon motif’s such as T-junctions, to try and elucidate the mechanisms behind self-assembly of complex origami.
By increasing our understanding of how DNA folds, design principles can then be applied towards constructions of functional origamis, of which there have been relatively few examples so far. A brave new world of DNA templated chemistry and molecular motors awaits!
By Dr Thomas Gorochowski and insights from PhD student Janine McCaughey and Research Associate Ulrike Obst.
On the 2nd October 2019, Professor Nico Sommerdijk visited Bristol for the monthly BBI seminar and provided a picture of the hidden nanoscale world underpinning biology. Nico, who describes himself as a synthetic organic chemist who got carried away when introduced to the expanding capabilities of electron microscopy (EM), has since then never looked back. His work spans the development and application of new EM imaging and microscopy methods to not only image molecular assemblies in a single static pose, but also to record movies that help unravel the steps involved in their self-assembly.
The seminar focused on the mineralisation of collagen fibril that act as the basic building block of our bones. The nanoscopic dimensions and complex, hybrid composition of mineralised collagen makes it difficult to examine. Trickier still is monitoring the multi-step process that collagen goes through to mineralise, as it forms not only at a billionth of a meter in scale, but also in an intricate, aqueous environment.
Why is understanding this process important?
Understanding the process of collagen mineralization could enable the development of new treatments for bone defects and disorders of bone mineralization, such as rickets and hypophosphatasia.
Nico highlighted that “it will also offer new opportunities for the design of new bio-inspired materials”. This can be in the form of an in vitro unit that can be biologically engineered to form mineralized collagen to precise specifications. Unravelling the minute process of mineralization could therefore benefit many branches of science, from medicine and pharmaceuticals to bioengineering.
What did the audience think?
Janine McCaughey from the School of Biochemistry explained that “Nico presented an interesting approach to enabling live cell TEM in form of a liquid chamber. This allows for imaging of dynamic processes in high resolution compared to cryoTEM that requires one sample per timepoint and therefore only delivers very limited insight into such processes”.
Ulrike Obst, a Research Associate from Cellular and Molecular Medicine, was amazed by the sheer scope of the work. “It was fascinating to find out about so many different electron microscopy techniques, and especially how they can be combined to observe dynamic biological processes at a nanoscale!”
Ulrike was also amused by this idea of “having a mini-aquarium in a microscope”, where a tiny pocket of water allows for molecular self-assembly to be watched in real-time. “It is crazy that such things are possible. It’s like a window into another world.”
Interested to find out more?
As part of his recent ERC Advanced Grant award titled “A Google Earth Approach to Understanding Collagen Mineralization”, Nico recently moved to the Radboud Institute for Molecular Life Sciences in Nijmegen, Netherlands (https://www.radboudumc.nl/en). As part of this project, his group will try to figure out how collagen is assembled by developing and combining methods able to image from the nano- to cellular-scales, providing an unprecedented understanding of this crucial biological process.
Scientists at the Bristol BioDesign Institute have combined synthetic biology with Oracle’s cloud computing software, engineering nanoparticles to create a new vaccine candidate against the mosquito-borne chikungunya virus.
What is chikungunya?
Chikungunya is an arbovirus which, like zika and dengue fever, is transmitted by mosquito bites. Its name derives from the East African Makonde language, meaning “to become contorted” due to the crippling effect that the virus has on the joints. Other symptoms include fever, nausea and fatigue. Chikungunya’s varying levels of severity, from a brief episode to weeks long debilitation, and even death in some cases, means that it is very commonly misdiagnosed. Currently, there are no available treatments or vaccines.
Where is it found?
Since its discovery in 1952, more than 60 countries have identified cases of chikungunya- mostly in Africa, Asia and the Indian subcontinent. “It is usually confined to sub-saharan Africa but because of deforestation and climate change it has started to spread all over the world”, says Prof. Imre Berger, a leading scientist on the vaccine publication. In the last year alone, there have been reports of mosquito-borne viruses including West Nile virus in Germany, dengue and chikungunya in Grenoble and Tarn, France, respectively.
“A major problem with vaccines at the moment is that they need to be refrigerated for storage and for transport, otherwise they become inactivated” Imre explains. This is what is known as a cold chain. Most vaccines, from polio to Hepatitis to the flu must be refrigerated, making the transferral of vaccines to remote or less affluent locations a real challenge.
Bypassing the cold chain problem.
Researchers at the Bristol Biodesign Institute, the French National Centre for Scientific Research (CNRS) and Imophoron Ltd have engineered a synthetic protein scaffold that could revolutionise the way that chikungunya vaccines are designed, produced and stored- without refrigeration.
To design this scaffold the collaborators created detailed 3D images of cryogenically frozen nanoparticles viewed through a high-resolution electron microscope, using high-performance cloud computing from Oracle.
How was the scaffold engineered?
“We have applied synthetic biology to engineer the surface of the ADDomerTM” (which the team have named the manipulated structure) says Imre. “By putting small and harmless pieces of the chikungunya virus on top of the surface of the ADDomer, we can create a particle which looks like chikungunya but it’s not.” This tricks the immune system into developing antibodies against the virus, effectively immunising the body before becoming exposed to the real thing.
The protein-based nanoparticle is a dodecahedron with a quasi-spherical shape capable of spontaneous self-organisation, which makes it ideal as a vaccine platform technology.
To understand the composition of the ADDomer at near-atomic resolution, massive amounts of cryo-electron microscope images of the protein were processed into Oracle’s cloud computing software to produce a single 3D structure.
What is cloud computing?
“Cloud computing fundamentally is the ability to be able to get computing or storage or networking access as a utility”, says Phil Bates, Oracle.
The unique combination of University of Bristol’s state-of-the-art cryo-electron microscopes used in conjunction with cloud computing meant that huge swathes of data could be analysed “in a fraction of the time and at much lower cost than previously thought possible” Dr Christopher Woods explains.
So how is it different to the other vaccine candidates?
“Completely by chance, we discovered that this particle was incredibly stable even after months, without refrigeration” explains Pascal Fender (CNRS). Unlike the previous chikungunya vaccine candidates, the ADDomer is thermostable- meaning that it can be stored for weeks at warm temperatures- thus eliminating the need for a cold chain.
Josh Bufton, from Bristol’s cryo-EM facility, says that “determining the structure of the ADDomer at near atomic resolution by cryo-Electron Microscopy allowed us to both validate the design of the ADDomer as an effective scaffold for vaccine development and gain insights into its exceptional thermostability.”
In short, the accuracy of cryo-electron microscopy, the speed and affordability of cloud computing and the synthetic engineering of the proteins has created a cheap, thermostable chikungunya vaccine candidate that can be produced en masse.
What does this mean?
“What we need to do now for the next step, is to continue the validation in other infectious disease areas and to continue to develop our technology” concludes Frederic Garzoni, Director of Imophoron Ltd. The viability of the ADDomer as a chikungunya vaccine candidate is just the beginning of addressing an entire universe of infectious diseases- both human and veterinary.
Imre adds “in our current paper, we already show more than a dozen other vaccine candidates which we have made. We now have more than 30 altogether and we are very interested to see how powerful our technology really is.”
Hosted by Dr Thomas Gorochowski and PhD students Veronica Greco and Matthew Tarnowski from the Biocompute Lab.
Dr Bert Poolman, a biochemist from the University of Groningen, visited Bristol on the 4th September to pose the question of whether it is possible to artificially create and control the physicochemistry of a cell. The ability to manipulate, control, or even create a new cell from scratch are fundamental directions for synthetic biology research.
What if we could build a cell in the lab?
Bert Poolman is part of an EU-wide project – aptly named BaSyC, or, ‘Building a Synthetic Cell’, which emerged in September 2017 combining leaders in physics, chemistry and biology from across the Netherlands to test out this theory.
“In the next decade they aim to achieve a physicochemical homeostatis in a cell where metabolic pathways and energy consumption/production systems can be better understood, optimised and synthetically built.” Veronica Greco explains. She was in the audience during his seminar.
Matthew Tarnowski, who also attended the seminar, said that Bert “highlighted some fascinating properties of cells: they are incredibly crowded, yet molecules move surprisingly fast within them.” Matthew was struck by Bert’s results demonstrating the sheer complexity of cells. “He [Bert] showed that engineering systems that mimic fundamental cellular processes is challenging”.
What was the audience reaction?
Intrigued audience members questioned the sustainability of such an ambitious project, such as how to overcome the challenge of building a synthetic ribosome and the new methods required to carefully assemble the numerous parts of a synthetic cell in a controllable way.
“The talk left me curious about how minimal life research could be completed responsibly: have the economic, social and environmental impacts been anticipated?” Matthew pointed out that the purpose behind building minimal forms of life went unanswered.
Veronica ended by noting that, “Overall, it is a very well thought out project that will require lots of different expertise and time, and surely it has all the credentials to give a big contribution to science and to change once again how the growing scientific field of synthetic biology is perceived.”
Are you a PhD or Postdoc?
BaSyC are offering various work packages to PhDs and Postdocs within one of their partner institutions. Due to the interdisciplinary nature of the work (combining physicists, chemists and biologists), “working at different locations and labs is more the rule than the exception”. There are opportunities to be involved in BaSyC activities: progress meetings and trainings, summer schools and the biennial international symposium on Building a Synthetic Cell.
No jobs available for the specific part of the programme you are interested in? Feel free to send an open application to the corresponding PI directly – the PI’s contact details can be found at their people page.
