Control-based Continuation of Solutions and Bifurcations in Dynamic-Clamp-Constructed Hybrid Bursting Systems

Lead Research Organisation: University of Bristol
Department Name: Engineering Mathematics

Abstract

Control theory is an interdisciplinary branch of engineering and mathematics that deals with the behaviour of dynamical systems. It is built up around a few very simple ideas, such as feedback loop and stability. Control theory concerns itself with means by which to alter the desired output of a system, called the reference. When one or more output variables of a system need to follow a certain reference over time, a controller manipulates the inputs to a system to obtain the desired effect on the output of the system. Systems can usefully be defined in almost any discipline - they are not confined to engineering or mathematics. The idea behind this proposal is to develop novel control techniques applicable to real biological cells. In particular, we are interested in the behaviour of excitable cells, described mathematically by nonlinear dynamical systems.Excitability of cells and tissues is a basic function of life. It is the ability of cells to respond to stimuli. Excitability is necessary for the functioning of nerves, muscles, and hormones, among other things. The basis for the excitability of cells is their ion distribution, and the distribution of ions and molecules is determined by transport mechanisms associated with their plasma membrane structure. This structure permits and regulates various forms of ionic and molecular transport. The ability of experimentalists to perturb biological systems has traditionally been limited to rigid pre-programmed protocols or more flexible, but reflex constrained, operator-controlled protocols. In contrast, real-time control allows the researcher to dynamically probe a biological system with parameter perturbations that are calculated functions of instantaneous system measurements, thereby providing the ability to address diverse unanswered questions that are not amenable to traditional approaches.There is a great deal of experimental data on one hand and a wealth of theoretical knowledge about excitable systems on the other. This project aims to bridge the gap between theory and experiments by exploring and designing novel techniques for investigation and control of excitable cell systems in real experimental settings. In a long term, such a technology will open completely new avenues for research in development of effective therapies for diseases associated with excitable cell dysfunction.

Planned Impact

As well as the specific academic beneficiaries listed in the Academic Beneficiaries section, the public and a wider academic community will benefit from the increase in knowledge about basic excitable cell physiology and thus brain, heart and muscles function as well as regulation of hormonal secretion. This project also has a great scope towards the medical community, clinical neuroscience and public health. Sectors of the pharmaceutical industry working to develop effective drug therapies for diseases based on excitable cell disorders will also benefit from the proposed work. Indirectly, and in the long term, people suffering from such diseases may also benefit. Therefore, there is the potential for beneficial impact on both the health and wealth of the UK. The ability of an excitable cell to generate a response (in the form of action potential spike or burst) is an important guide to its health. Research into numerous diseases such as neurological disorders, high blood pressure, angina, abnormal heart rhythms, diabetes, etc. has found deficits in ion channels function and specifically the ability to correctly respond to stimuli. This has led to the current idea that these diseases may be classed as channelopathies . Therefore, the mechanisms that we will study in our research will be incorporated into the body of knowledge about these debilitating diseases, for example, informing the development of animal models of disease, which amongst other things, pharmaceutical companies extensively utilise as part of the drug development process. The social impact and economic costs of the diseases mentioned above are enormous. Therefore our work will benefit society from the advances we make in investigating mechanisms that may underlie such diseases, and will benefit the economy both in terms of costs saved in care for patients suffering from these conditions, and also in profits from pharmaceuticals developed and sold by UK-based companies. We acknowledge that these indirect benefits may take several years before they are realised. Following my recent appointment at the University of Bristol as a Lecturer in Engineering Mathematics, the impact of this award on my prospects, as an independent researcher, will be large as it will allow me to start up my intended research programme. The proposed study is highly ambitious, and will draw on the experience of leading researchers at the University of Bristol. It will use interdisciplinary approaches, such as mathematical modelling, computer programming and iterative cycles with wet-lab experiments to validate the models and test model predictions. I have personally developed and analysed the models to be used in this study, and this project will allow me to gain further knowledge and develop a number of new skills. Due to its unprecedented character this project will most likely lead to a number of high impact publications to be generated in the course of the work.
 
Description The research funded on EP/I018638/1 grant has contributed to our understanding of how to design and analyse hybrid systems interfacing a living system (such as biological cell, organ, tissue, or a human being) with computer program implementing mathematical formulation of an important dynamic component of the living system under investigation.
Exploitation Route Some of the ideas developed as part of EP/I018638/1 have been now used in one of my current research grants:

01/02/2013 - 31/01/2016 (PI - Exeter)
EU FP7 ICT 2.9 - Cognitive Sciences and robotics (€2,900,000) collaborative project, Title: AlterEgo: Enhancing social interactions using information technology, coordinated by Prof Benoît Bardy at Montpellier 1 University in France. The project also involves computer science experts from the DFKI centre (Germany), roboticists from the Ecole Polytechnique Fédérale de Lausanne (CH), as well as clinicians, psychologists and psychiatrists from the Academic Hospital of Montpellier (CHRU, FR).
Sectors Digital/Communication/Information Technologies (including Software),Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description EPSRC Centres for Mathematical Sciences in Healthcare
Amount £2,008,955 (GBP)
Funding ID EP/N014391/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 01/2016 
End 12/2019
 
Description EPSRC Impact Acceleration Account (IAA) Impact and Knowledge Exchange Award
Amount £65,942 (GBP)
Funding ID Pfact ID: 9372 
Organisation University of Exeter 
Sector Academic/University
Country United Kingdom
Start 03/2018 
End 09/2018
 
Description EU FP7
Amount € 2,900,000 (EUR)
Funding ID 600610 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 02/2013 
End 01/2016
 
Description AlterEgo: Enhancing social interactions using information technology 
Organisation University of Montpellier
Country France 
Sector Academic/University 
PI Contribution Partner on the EU grant
Collaborator Contribution Coordinating the EU grant
Impact Collaborative project, Title: AlterEgo: Enhancing social interactions using information technology, coordinated by Prof Beno?t Bardy at Montpellier 1 University in France. The project also involves computer science experts from the DFKI centre (Germany), roboticists from the Ecole Polytechnique F?d?rale de Lausanne (CH), as well as clinicians, psychologists and psychiatrists from the Academic Hospital of Montpellier (CHRU, FR).
Start Year 2011
 
Description Engagement with Avon and Wiltshire Mental Health Partnership NHS Trust and Devon Partnership NHS Trust 
Organisation Avon and Wiltshire Mental Health Partnership NHS Trust
Country United Kingdom 
Sector Public 
PI Contribution We are contributing novel methodology that could potentially help the South West NHS Mental Health Trusts with early diagnosis of psychosis. This is based on real-time human virtual partner interaction and inspired by ideas developed as part of the EPSRC funding I an reporting on.
Collaborator Contribution The Avon and Wiltshire Mental Health Partnership NHS Trust and Devon Partnership NHS Trust are contributing access to their Early Intervention Teams, in-kind funding support and expertise.
Impact We have secured funding to perform a pilot study involving both, Avon and Wiltshire Mental Health Partnership NHS Trust and Devon Partnership NHS Trust. The collaboration is multidisciplinary and involves, mathematicians, clinical psychologists and psychiatrists.
Start Year 2017
 
Description Engagement with Avon and Wiltshire Mental Health Partnership NHS Trust and Devon Partnership NHS Trust 
Organisation Devon Partnership NHS Trust
Country United Kingdom 
Sector Public 
PI Contribution We are contributing novel methodology that could potentially help the South West NHS Mental Health Trusts with early diagnosis of psychosis. This is based on real-time human virtual partner interaction and inspired by ideas developed as part of the EPSRC funding I an reporting on.
Collaborator Contribution The Avon and Wiltshire Mental Health Partnership NHS Trust and Devon Partnership NHS Trust are contributing access to their Early Intervention Teams, in-kind funding support and expertise.
Impact We have secured funding to perform a pilot study involving both, Avon and Wiltshire Mental Health Partnership NHS Trust and Devon Partnership NHS Trust. The collaboration is multidisciplinary and involves, mathematicians, clinical psychologists and psychiatrists.
Start Year 2017
 
Description Brain Awareness Week, public talk on 15th March 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact The Brain Awareness Week is a global campaign which aims to increase the public's awareness of current brain research. It is taking place from the 12 - 18 March 2018 and the University of Exeter has been awarded funding from the British Neuroscience Association to host a range of workshops and events on brain-related topics. One of our public events is called "Neuroscience: Is it all in our minds?", which is a seminar series introducing a diverse audience to a range of neuroscience ideology and research findings, with an opportunity for questions and networking.
Year(s) Of Engagement Activity 2018
 
Description Interview for the Euro News channel feature 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact During the final workshop for the FP7 funded EU project "AlterEgo", the Euronews channel filmed this interview.
Year(s) Of Engagement Activity 2016
URL http://www.euronews.com/2016/10/31/avatars-help-schizophrenia-patients-silence-tormenting-voices
 
Description Real-time dynamic sub-structured testing and control of living systems 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Popularising my research amongst general public

Discussions
Year(s) Of Engagement Activity 2011
 
Description Soapbox Science Speaker on the 14th of June 2014 in Bristol 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact This activity was a joined effort with the Bristol Festival of Nature that transformed the city's open spaces into a hub of scientific learning and discussion, as some of the UK's leading female scientists took to their soapboxes to showcase science to the general public. The event's mission remains the same: to help eliminate gender inequality in science by raising the profile, and challenging the public's view, of women and science (http://soapboxscience.org/?page_id=823)
Year(s) Of Engagement Activity 2014
URL http://soapboxscience.org/?p=1149