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EEBio: Efficient Engineering and Control of Predictable and Reliable Biosystems

Lead Research Organisation: University of Oxford
Department Name: Engineering Science

Abstract

Research at the intersection of biology and engineering has expanded our understanding of living systems and the many unique and valuable capabilities they possess. Scientists and engineers have now begun to harness this knowledge in new ways to address some of humanity's most pressing challenges. For example, using engineered biosystems we can create innovative healthcare solutions, enable more sustainable forms of agriculture, and support clean manufacturing methods. The emerging field of Engineering Biology aims to harness biology to build technologies for a healthy, sustainable, and equitable future. However, to date the lack of a rigorous biological engineering process has resulted in biosystems that are fragile, unpredictable, and difficult to scale when applied in real-world settings.

Early pioneers in fields ranging from Aerospace to Information Technologies faced similar challenges when attempting to create robust and reliable systems. Such difficulties were oftentimes overcome using methods from systems and control engineering, which enabled rigorous approaches to the design, optimisation, and realisation of engineered systems, ultimately leading to dramatic economic growth and the creation of entirely new industries. To achieve an equivalent step-change in the engineering of reliable and robust biological systems, our programme will develop similar control and Artificial Intelligence systems in biotechnology - which we term feedback biocontrollers. These biocontrollers will be designed to operate within cells, between cells, and even to interact with non-biological entities (such as computers), thereby allowing researchers and innovators to efficiently and safely harness engineered biology in its many real-world applications.

The robust engineering of biological control systems will be underpinned by the development of four "Engineering Pillars". These cover Theory (mathematical/AI approaches based on systems and control theory to model, design, analyse, and optimise biosystems), Software (computational tools able to translate this theory into conceptual designs), Wetware (experimental methods and biological parts to make designs a biological reality), and Hardware (to comprehensively test, scale-up, and deploy engineered biosystems). Each Pillar feeds directly into an integrated "Design-Build-Test-Learn" cycle rooted in systems and control engineering methods, which will accelerate academic and industrial development of new biotechnologies. Technologies developed in each Engineering Pillar will be integrated to address outstanding problems in three "Grand Challenge'' application domains: Biomedicine, Agriculture, and the Environment. Our team will work with industrial partners to generate world-leading solutions for each of these areas, demonstrating how biocontrollers can revolutionise scale-up and deployment of reliable engineered biotechnologies.

The EEBio programme represents a timely investment in the new field of Engineering Biology which is set to play a defining role in the future of our society and the rapidly growing Bioeconomy. Our team of world-leading experts and up-and-coming early career researchers will create tools and technologies that are key to the effective engineering of biological systems - as observed in other, mature engineering fields - but which are not yet realised for Engineering Biology. EEBio brings together recent momentum across our team for rapid impact, while also supporting development of seminal ideas; in the near-term this will help address Grand Challenges we face today, while in the long-term it will provide the foundation for many bio-based solutions that will improve human life, agriculture, and the environment. Our work will accelerate responsible industrial exploitation, open up the field to other research communities (in the life, medical and social sciences), and support public confidence in the safety and reliability of Engineering Biology.
 
Description Dr Ceroni was an invited speaker at the Nuffield Council on Bioethics (NCOB) workshop to explore the emerging and potential future ethical challenges of engineering biology
Geographic Reach National 
Policy Influence Type Contribution to a national consultation/review
URL https://www.nuffieldbioethics.org/news-blog/embedding-ethics-into-the-engineering-biology-pipeline/
 
Description Nuffield Council on Bioethics (NCOB) workshop to explore the emerging and potential future ethical challenges of engineering biology
Geographic Reach National 
Policy Influence Type Contribution to a national consultation/review
URL https://www.nuffieldbioethics.org/news-blog/embedding-ethics-into-the-engineering-biology-pipeline/
 
Description Oral evidence from Professor Lucia Marucci to the House of Lords Science and Technology Committee report titled 'Don't fail to scale: seizing the opportunity of engineering biology'
Geographic Reach National 
Policy Influence Type Contribution to a national consultation/review
URL https://committees.parliament.uk/oralevidence/14637/html/
 
Description Prof Papachristodoulou was interviewed for the BBSRC Synthetic Biology for Growth programme economic impact evaluation report
Geographic Reach National 
Policy Influence Type Contribution to a national consultation/review
URL https://www.ukri.org/wp-content/uploads/2024/10/BBSRC-031024-SyntheticBiologyGrowthProgrammeEconomic...
 
Description Written evidence from Dr Rodrigo Ledesma-Amaro to the House of Lords Science and Technology Committee report titled 'Don't fail to scale: seizing the opportunity of engineering biology' (ENB0026)
Geographic Reach National 
Policy Influence Type Contribution to a national consultation/review
URL https://committees.parliament.uk/writtenevidence/130240/html
 
Description Written evidence from Professor Harrison Steel and colleagues to the House of Lords Science and Technology Committee report titled 'Don't fail to scale: seizing the opportunity of engineering biology' (ENB0018)
Geographic Reach National 
Policy Influence Type Contribution to a national consultation/review
URL https://committees.parliament.uk/writtenevidence/130232/html
 
Title Quantum Spin Resonance in Engineered Magneto-Sensitive Fluorescent Proteins Enables Multi-Modal Sensing in Living Cells 
Description Quantum mechanical phenomena have been identified as fundamentally significant to an increasing number of biological processes. Simultaneously, quantum sensing is emerging as a cutting-edge technology for precision biosensing. However, biological based candidates for quantum-sensors have thus far been limited to in vitrosystems, are prone to light induced degradation, and require sophisticated experimental setups making high-throughput studies prohibitively complex. We recently created a new class of magneto-sensitive fluorescent proteins (MFPs) [1], which we now show overcome these challenges and represent the first biological quantum-based sensor that functions at physiological conditions and in living cells. Through directed evolution, we demonstrate the possibility of engineering these proteins to alter properties of their response to magnetic fields and radio frequencies. These effects are explained in terms of the spin correlated radical pair (SCRP) mechanism, involving the protein backbone and a bound flavin cofactor. Using this engineered system we demonstrate the first observation of a fluorescent protein exhibiting Optically Detected Magnetic Resonance (ODMR) in living bacterial cells at room temperature, at sufficiently high signal-to-noise to be detected in a single cell, paving the way for development of a new class of in vivo biosensors. Magnetic resonance measurements using fluorescent proteins enable unprecedented technologies, for instance 3D spatial localisation of the fluorescence using gradient fields (i.e. Magnetic Resonance Imaging but using an endogenous probe). We further demonstrate the use of multiple variants of MFPs for multiplexing or lock-in amplification of fluorescence signals, opening a new approach to combining or extracting multiple signals from a biological measurement. Taken together, our results represent a new intersection of imaging and perhaps actuation modalities for engineered biological systems, based on and designed around understanding the quantum mechanical properties of MFPs. 
Type Of Material Database/Collection of data 
Year Produced 2024 
Provided To Others? Yes  
URL https://zenodo.org/doi/10.5281/zenodo.14495634
 
Description EEBio 1st Project meeting and Industry Forum 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact The first in a series of annual project meetings, serving also as the formal launch the EEBio project. Industry representatives were invited to an additional industry forum focussed on identifying challenges faced by industry understanding how collaborative research with project members under EEBio could develop solutions.
Year(s) Of Engagement Activity 2024
URL https://eebio.ac.uk/events
 
Description Lubbock Lecture 2024: Professor Antonis Papachristodoulou - Designing Biocontrollers 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact 70 people attended the Lubbock Lecture 2024, which featured a presentation by Professor Antonis Papachristodoulou. His lecture sparked engaging questions and discussions about the revolutionary design of Biocontrollers. Additionally, the lecture was recorded and published on YouTube, where it has received 232 views to date.
Year(s) Of Engagement Activity 2024
URL https://www.youtube.com/watch?v=6nBK5Au3Xq4
 
Description Lubbock Lecture 2024: Professor Harrison Steel - Robotics & Control meet Synthetic Biology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact 70 people attended the Lubbock Lecture 2024, which featured a presentation by Professor Harrison Steel. His lecture sparked engaging questions and discussions about the promising future of engineering biology. Additionally, the lecture was recorded and published on YouTube, where it has received 405 views to date.
Year(s) Of Engagement Activity 2024
URL https://www.youtube.com/watch?v=5DFZ9xmeqPs
 
Description Prof Steel acted as a judge at a Nucleate Startup Competition 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact This involved several rounds of mentoring of student start-ups in Biotech from around the UK. Then formed part of a panel which listened to their pitches and selected winners. They covered engineering biology through to instrumentation and medical applications.
Year(s) Of Engagement Activity 2024
URL https://nucleate.org/
 
Description Prof Steel and colleagues presentated at SynBio Oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact Attended by about 50 undergrads, we reported on different research projects under SYnBio to engage students in research and hopefully bring them for internships/future work and collaboration.
Year(s) Of Engagement Activity 2024
URL https://synbio-ox.github.io/synbiooxford/
 
Description Synthetic Biology Society Talk by Hayley Knights 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact A member of the Oxford Synthetic Biology Society invited me to give a talk on how we are applying synthetic biology tools to engineer bacteria as bioinoculants in agriculture, titled 'Engineering nitrogen-fixing symbiosis between cereals and bacteria'. After the talk students asked questions and we had more general discussions about this area of research. It was mentioned that most members of the society are from a biochemistry background and so this was the first talk they had relating to plant-microbe interactions. It also led to one student contacting me about doing their 4th year masters project with me.

The talk made the students aware of wider applications for synthetic biology which they had not come across from their lectures.
Year(s) Of Engagement Activity 2024