LIVEBIO: Light-weight Verification for Synthetic Biology

Lead Research Organisation: University of Bradford
Department Name: Faculty of Engineering and Informatics

Abstract

The 21th century will be the age of Biology, tackling global challenges, including -but not limited to- understanding and curing diseases, repairing defective genes, combining natural and synthetic tissues, enhancing crops with biotechnologies, reproducing organs using stem cells, etc. [Chief Scientific Adviser to The President of the EU Commission].

Synthetic Biology (SB), referring to the design and engineering of biological components and systems that do not already exist in the natural world, will play a key role in addressing these challenges by providing a radical step-change in our ability to design and construct multi-scaled biological systems.

Along with the advances in the wet lab and computational methods, the functionality and complexity of SB systems are steadily growing, which brings in a major issue: the likelihood that faults and flaws existent in these systems. This can result in the construction of bio-parts and components that are faulty by design.

At the moment, there are no established methods in SB to find errors and verify correctness. The current practice is limited to understanding the sub-cellular molecular machinery in wet-lab environments, which is costly and extremely slow. The existing computational approaches for analysing biological processes mainly rely on simulation; but many important system properties cannot be inferred using this method. Also, simulation tells the "existence of errors, not their absence". So, it is not an efficient method to guarantee the system correctness.

LIVEBIO aims to pave the way for the next generation verification of large and complex synthetic bio-systems. The novel approach proposed in this project will permit rapid verification of complex SB systems, and provide increased assurance and trust when building new synthetic biology systems. The project will deliver an authentic and systematic certification guideline, which will allow biologists to certify their genetic parts & components and reuse them in different systems.
LIVEBIO will contribute towards biological studies (in particular, Synthetic Biology) by extending the existing portfolio of computational approaches with novel verification methods, techniques and tools. It will also contribute towards Computer Science by developing cutting-edge activities through an emerging and promising inter-disciplinary work. The impact will go beyond the project partners, and will reach national and international communities.

Planned Impact

The project outcomes will initiate a huge impact on Synthetic Biology (SB) via novel computing solutions that will allow constructing reliable, fault-free and reusable bio-systems. This will significantly reduce the costs required to develop new synthetic organisms. The project will benefit regulators and regulation bodies via a certification mechanism that will enhance the route towards standardisation and regulation compliance for Synthetic Biology.

The project will contribute to strengthening the leading role of the UK in Formal Methods and Synthetic Biology, as well as creating a wide range of novel research outputs in other relevant fields of Computer Science. The work to be carried out will lead to high impact publications on world-leading conferences and journals, attracting grants and investment from both research councils and industry, and establishing a long-term research and industry partnerships in this emerging research area. The research will have an impact on project partners and other academic beneficiaries through the generation of new knowledge, new discovery, new-engineered systems, and other exciting developments.

The knowledge, expertise and capability gained will be transferred through knowledge exchange to stimulate this impact on the UK economy. The new computational approaches to the analysis of complex bio-systems will result in novel approaches for engineering SB systems. This has clear commercial value and will contribute increasing productivity. This will open new avenues for product development and the application of SB in a wide range of industrial domains, e.g. pharmacology and bio-manufacturing.

As well as academic and economic impact, this research will also have a valuable social impact. The ultimate beneficiaries of the project are the general public. It will contribute to our ability to rapidly adopt new technologies for chronic and infectious diseases and to accelerate discovery science, e.g., in drug development and anti microbial materials. It will also help making basic SB available to people in a safe and controlled environments without working in a wet lab.

The project will also have an impact on life science researchers, PhD students and young software engineering professionals via training courses and seminars that will transfer the necessary skills and expertise. It will especially target closing the skill gap to use software engineering and high-performance computing facilities within scientific research. Our results and examples will be incorporated in several modules both across Engineering and the Life Sciences. It will conveniently help us develop new curriculums and programmes within both faculties, as well as implement joint study programmes for graduates and undergraduates.

The project will extend an interdisciplinary collaboration portfolio across the University. This will resonate with Bradford's strategic vision in the key academic themes of advanced healthcare and innovative engineering. The project also supports the University's strategic plan of making Bradford the Technology University of the North.

Publications

10 25 50
 
Description We have developed a computational modelling and analysis framework that combines rule-based systems (P systems), agent-based simulation, high-performance computing and formal verification. We have also developed a software tool that enables creating general membrane computing models, integrating the most used concepts presented in the literature, and analysing them using (high-performance) simulation and model checking.

We have developed the Infobiotics Workbench (IBW), a user-friendly, scalable, and integrated computational environment for the computer-aided design of synthetic biological systems. It supports an iterative workflow that begins with specification of the desired synthetic system, followed by sim- ulation and verification of the system in high-performance environments and ending with the eventual compilation of the system specification into suitable genetic constructs. IBW is currently the only platform that integrates modelling, simulation, verification and biocompilation features into a single software suite.

We have also developed a light, user-friendly and efficient web-based version of IBW, combining all the features and functionalities stated above and running on HPC and GPU-based servers, offering a seamless experience for users. This application is one of the few web-based synthetic biology workbench tools currently available.

In addition, we have also developed an agent-based, off-lattice, real-time, 3D multicellular simulation software for simulating physical dynamics of biological populations.
Exploitation Route The project has resulted in significant important outcomes, and produced one of the most efficient and useful tools for modeling and analysing synthetic biology systems. The tool is compatible with well-known data exchange formats and data libraries. However, the technology developed is still not ready to incorporate the actual lab data. Using AI and ML technologies, our tool can be extended to incorporate actual lab results and address more challenging use cases, especially emerged from pharmaceutical industry (e.g., drug development and design).

Another important direction to take these research outcomes forward is generating automated models. This is a very promising research direction, and can leap the current state-of-the-art in biotechnology research.
Sectors Digital/Communication/Information Technologies (including Software),Pharmaceuticals and Medical Biotechnology,Other

 
Description The project has resulted in: - two PhD projects (one ending September 2023) - several UG/PG projects - part-time student projects (funded by a university internal grant) - several public events (e.g., British Science Week), open days, applicant experience days - public presentations (e.g. West Yorkshire Innovation Festival) - used some of the techniques/methods in KTP projects (two certificate of excellence awards, one KTP Best of Best) - new networks and connections through workshops including the businesses - currently in the process of setting up a spin out company, but the process is ongoing - also planning to give a media interview within the next couple of months
First Year Of Impact 2022
Sector Digital/Communication/Information Technologies (including Software),Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic

 
Description Innovate UK KTP
Amount £187,000 (GBP)
Funding ID KTP012139 
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 03/2020 
End 06/2022
 
Description Made Smarter Innovation
Amount £610,168 (GBP)
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 10/2022 
End 09/2024
 
Title Infobiotics Workbench Tool 
Description The first release of Infobiotics Workbench was done. Infobiotics Workbench (IBW) - a computer-aided design suite for synthetic biology that assists the synthetic biologist in an informed, iterative workflow of system specification, verification, simulation and biocompilation. IBW incorporates well-established design principles that guide both experienced and non-experienced biologists in refining a putative functionality into a formally-specified document for fabricating a nucleotide sequence after undergoing verification and simulation. 
Type Of Material Improvements to research infrastructure 
Year Produced 2021 
Provided To Others? Yes  
Impact The tool is available to all academic and industry community. The workbench adopts well-established design principles that guide both experienced and non-experienced biologists in refining a putative functionality into a formally-specified document for fabricating a nucleotide sequence after undergoing some computational analysis. This will result in huge cost savings by reducing the number of wet-lab experiments. 
URL https://infobiotics.org
 
Title Computational models of some case studies 
Description We provide a number of case studies and computational models (including synthetic biology) for kPWorkbench tool membrane computing 
Type Of Material Computer model/algorithm 
Year Produced 2020 
Provided To Others? Yes  
Impact Users can easily test these models and do some experiments using the models provided 
URL https://github.com/Kernel-P-Systems/kPWorkbench/wiki/Case-Studies
 
Title Computational models of some synthetic biology case studies 
Description We provide a number of case studies and computational models (including genetic logic gates, toggle switch, repressilator and quorum sensing) for Infobiotics Workbench tool. 
Type Of Material Computer model/algorithm 
Year Produced 2021 
Provided To Others? Yes  
Impact Biologists can create computational models similar to these models. They can construct their genetic designs as a computer model and carry out a number of computational analysis to make sure if the engineered bacteria exhibit the desired behaviour before implementing them in wet lab. 
URL https://infobiotics.org/_static/case_studies_461334.zip
 
Description Computational Biology Research Group, Brunel University 
Organisation Brunel University London
Department School of Information Systems, Computing and Mathematics
Country United Kingdom 
Sector Academic/University 
PI Contribution This collaboration has been established through Prof. David Gilbert, Prof Monika Heiner and Dr Robin Donaldson. Prof Gilbert led the Computational, Mathematical & Statistical Synthetic Biology section of the Synthetic Biology theme in the Institute of Environment, Health and Societies. The collaboration involves integrating some tools and methods developed by Prof. Gilbert's team into Infobiotics Workbench (IBW) platform. Our team will further modify/change these systems, which will enhance the capabilities of the IBW.
Collaborator Contribution Our collaborator, Prof Natalio Krasnogor from from Newcastle University, facilitated this collaboration.
Impact This interdisciplinary collaboration will allow the integration of some standalone computational tools (normally used by computer scientists) into the Infobiotics Workbench through translators, which will make them accessible to biologists.
Start Year 2022
 
Description Faculty of Mathematics and Computer Science, University of Bucharest 
Organisation University of Bucharest
Country Romania 
Sector Academic/University 
PI Contribution We have defined a synthetic biology domain language, which formally represents a stochastic membrane systems. We introduced simulation, verification and testing methods to formally analyse these models.
Collaborator Contribution Prof. Ipate and his team provided expertise in theoretical analysis of formal models, e.g. membrane systems, automata.
Impact 2 journal papers 1 joint PhD supervision
Start Year 2019
 
Description Membrane computing models: implementations 
Organisation Chengdu University of Technology
Country China 
Sector Academic/University 
PI Contribution The team produced a monograph on membrane computing models. I wrote to the sections on Systems and Synthetic Biology.
Collaborator Contribution The collaborators contributed to the different sections of the book.
Impact One monograph. The partners also submitted an EU project.
Start Year 2020
 
Description Membrane computing models: implementations 
Organisation Friedrich Schiller University Jena (FSU)
Country Germany 
Sector Academic/University 
PI Contribution The team produced a monograph on membrane computing models. I wrote to the sections on Systems and Synthetic Biology.
Collaborator Contribution The collaborators contributed to the different sections of the book.
Impact One monograph. The partners also submitted an EU project.
Start Year 2020
 
Description Membrane computing models: implementations 
Organisation University of Paris-Est
Country France 
Sector Academic/University 
PI Contribution The team produced a monograph on membrane computing models. I wrote to the sections on Systems and Synthetic Biology.
Collaborator Contribution The collaborators contributed to the different sections of the book.
Impact One monograph. The partners also submitted an EU project.
Start Year 2020
 
Description Membrane computing models: implementations 
Organisation University of Seville
Country Spain 
Sector Academic/University 
PI Contribution The team produced a monograph on membrane computing models. I wrote to the sections on Systems and Synthetic Biology.
Collaborator Contribution The collaborators contributed to the different sections of the book.
Impact One monograph. The partners also submitted an EU project.
Start Year 2020
 
Description University of Bradford - Synthetic Biology Lab 
Organisation University of Bradford
Department School of Life Sciences Bradford
Country United Kingdom 
Sector Academic/University 
PI Contribution The collaboration with the Synthetic Biology lab led by Dr Refaat Hamed (whose work is funded by BBSRC) at School of Chemistry and Bioscience, University of Bradford involves a joint supervision of 2 PhD students. This interdisciplinary collaboration is aiming at developing novel methods encapsulating both in-silico and in-vivo approaches in synthetic drug design. One of the important objectives is to embed more in-silico methods in wet-lab experiments to reduce the cost of experiments.
Collaborator Contribution The collaboration involves providing training to our PhD students on synthetic biology experiments in actual wet lab environments. The cost of this training is covered by my collaborator, which is worth £4,000.
Impact Joint PhD supervision of 2 students.
Start Year 2020
 
Description Vellore Institute of Technology 
Organisation Vellore Institute of Technology University
Country India 
Sector Academic/University 
PI Contribution We are currently working on developing a general Spiking Neural P Systems model that is generic enough to model synthetic biology systems. My team's main contribution will be on developing verification methods for this new system.
Collaborator Contribution We are currently working on developing a general Spiking Neural P Systems model that is generic enough to model synthetic biology systems. The partner team's main contribution will be developing new solutions to arithmetic and logical operations, as well as on NP-complete problems using variants of SNP systems.
Impact This collaboration led to institutional level collaboration. Two universities will sign a MoU, and start a student exchange programme (mainly PGR students).
Start Year 2022
 
Title Infobiotics Workbench 
Description Infobiotics Workbench (IBW) - a computer-aided design suite for synthetic biology that assists the synthetic biologist in an informed, iterative workflow of system specification, verification, simulation and biocompilation. IBW incorporates well-established design principles that guide both experienced and non-experienced biologists in refining a putative functionality into a formally-specified document for fabricating a nucleotide sequence after undergoing verification and simulation. 
Type Of Technology Software 
Year Produced 2021 
Open Source License? Yes  
Impact The tool is available to all academic and industry community. The workbench adopts well-established design principles that guide both experienced and non-experienced biologists in refining a putative functionality into a formally-specified document for fabricating a nucleotide sequence after undergoing some computational analysis. This will result in huge cost savings by reducing the number of wet-lab experiments. 
URL https://infobiotics.org
 
Title Infobiotics Workbench (Web) 
Description Infobiotics Workbench Web is a web-based version of (IBW), which is a computer-aided design suite for synthetic biology that assists the synthetic biologist in an informed, iterative workflow of system specification, verification, simulation and biocompilation. IBW incorporates well-established design principles that guide both experienced and non-experienced biologists in refining a putative functionality into a formally-specified document for fabricating a nucleotide sequence after undergoing verification and simulation. 
Type Of Technology Webtool/Application 
Year Produced 2023 
Open Source License? Yes  
Impact IBW Web is a light-weight, user-friendly and very efficient tool. It will significantly uplift the efficiency of in-silico executions as it relies on HPC and GPU devices to execute the computations 
URL https://infobiotics.org
 
Title UnrealMulticell3D 
Description UnrealMulticell3D is an agent-based, off-lattice, real-time, 3D multicellular simulation software developed in Epic Games' Unreal Engine 4 (UE4) and C++. UM3D addresses inferior graphical solutions with the state of the art 3D UE4 used for blockbuster gaming productions. UE4 provides GPU support for physics calculations utilizing PhysX which works with GeForce GPUs and performs Newtonian physics. 
Type Of Technology Software 
Year Produced 2022 
Open Source License? Yes  
Impact The research is connected to Synthetic Biology, which involves the editing of the genetic code, like Genetic Engineering. The genetic script controls the way that cells work structurally and functionally, all due to chemical changes, and the Unreal Multicell 3D simulator captures the resulting physical changes in terms of cellular organization that result from changes to the cells' operations. The simulator orchestrates these changes via sub-models that we sought to implement into an increasingly universal, flexible platform. Biological systems are by their very nature self-organizing, and the work alludes to tissue patterning, morphogenesis and functional studies through computer assisted design. 
 
Title kPWorkbench software tool 
Description We have developed the kPWorkbench software framework to support membrane computing and its applications. The tool offers unique features, including modelling, simulation, agent-based high performance simulation and verification, which allow modelling and computational analysis of membrane systems. 
Type Of Technology Software 
Year Produced 2020 
Open Source License? Yes  
Impact kPWorkbench integrates several state-of-the-art simulation and verification tools and methods. Featuring multiple simulators, using a native process and agent-based approaches relying on sequential and high performance execution, is very unique in this field. These features allow kPWorkbench to efficiently express problems studied with other classes of membrane systems, consequently analyse them via simulation and verification and decide on the best solutions. 
URL https://www.sciencedirect.com/science/article/pii/S2352711019302584
 
Description British Science week 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact We have been invited by the Science and Media Museum to develop an activity for the British Science week. The activity has been intended to engage with 13+ years pupils (and their parents) and encourage them to study the similar disciplines. Namely, we developed a multicellular biology simulator, Unreal Multicell 3D, built at Bradford University using a game engine.

The activity brief is summarized as follows: All life is made up of cells; tiny machines that can do amazing things, like make you walk and talk. Here you will see how we created computerized cells to act together in communities in many exciting ways depending on how they are designed. We can also create fun, multicellular animations by changing the cell settings in the cell editor. You see, different cells have different shapes and functions and we put this idea into our simulator. It is these differences that make the cell communities behave differently and scientific researchers want to understand and simulate different forms of life at the cell level. Cells like bacteria, and even human cells can be put into a computer simulation to create patterns and look at the way that tissues and colonies, which are groups of cells, behave. Using such simulators, scientists can look towards designing and understanding biological systems better, and computer scientists can help biology research and education by making simulators like this.
Year(s) Of Engagement Activity 2022
 
Description British Science week 2023 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact We have been invited by the Science and Media Museum to develop an activity for the British Science week. The activity has been intended to engage with 13+ years pupils (and their parents) and encourage them to study the similar disciplines. Namely, we developed a multicellular biology simulator, Unreal Multicell 3D, built at Bradford University using a game engine. The activity brief is summarized as follows: All life is made up of cells; tiny machines that can do amazing things, like make you walk and talk. Here you will see how we created computerized cells to act together in communities in many exciting ways depending on how they are designed. We can also create fun, multicellular animations by changing the cell settings in the cell editor. You see, different cells have different shapes and functions and we put this idea into our simulator. It is these differences that make the cell communities behave differently and scientific researchers want to understand and simulate different forms of life at the cell level. Cells like bacteria, and even human cells can be put into a computer simulation to create patterns and look at the way that tissues and colonies, which are groups of cells, behave. Using such simulators, scientists can look towards designing and understanding biological systems better, and computer scientists can help biology research and education by making simulators like this.
Year(s) Of Engagement Activity 2023
 
Description Innovate Local West Yorkshire 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Industry/Business
Results and Impact We gave a presentation on our projects and technologies we were developing. We also had a stand in the exhibition. We talked to a number of different businesses and arranged follow-up meetings. We are now working on some proposals with these businesses.
Year(s) Of Engagement Activity 2022
 
Description Interview with a magazine 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Interviewed by a national magazine, which has an international outreach. The interview sparked interest from industry and academy, who contacted via LinkedIn and other social media and informed their interest.
Year(s) Of Engagement Activity 2021
 
Description Invited talk to an international conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited keynote speaker at a prestigious International Conference, held in China. Several interesting comments and questions during and after the conference. The conference organizers invited for another keynote speech to be held in Seul, South Korea.
Year(s) Of Engagement Activity 2020
 
Description Life Science Interdisciplinary Seminar Series 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Study participants or study members
Results and Impact Invited speaker to an interdisciplinary workshop event organised by Faculty of Life Sciences, University of Bradford. The event triggered a lot of questions and interest to make collaboration.
Year(s) Of Engagement Activity 2020
 
Description Open Days 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact We have hosted in the region of 100 students in Open Days. We have presented our research to the pupils. They were very much surprised how computer scientists work with researchers from other disciplines. The schools are planning to bring more students in 2020.
Year(s) Of Engagement Activity 2019
 
Description Principle Healthcare Group 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Industry/Business
Results and Impact Principle Healthcare Group is one of Europe's Leading Providers of Vitamins, Minerals & Nutritional Supplements. We discussed the academia-industry collaboration opportunities and possible knowledge exchange projects
Year(s) Of Engagement Activity 2019