In vivo integral feedback control for robust synthetic biology

Lead Research Organisation: City University London
Department Name: Sch of Social Sciences

Abstract

Biotechnology companies use single cells (bacteria, yeast, or mammalian) as 'cell factories' to produce molecules of use in many different sectors, such as pharmaceuticals, enzymes, biofuels, cosmetics or fragrances. In some cases this means that compounds that were previously produced from non-renewable sources (petroleum) can be produced from renewable sources. In other cases cell factories produce useful compounds that would be impossible, too difficult, or too expensive to produce in other ways (e.g. using chemistry). To date, innovation for biotechnological processes has focused on maximising output, but now the challenge is to use cell factories more efficiently by reducing the required input of energy and nutrients. Moreover, as we learn more about how to design and control living cells, we can begin to envision new exciting potential uses for these 'living machines', especially in the healthcare sector.

In order to do this, we need to be able to engineer living cells that behave controllably in the face of changing conditions. This is what this project aims to achieve. In electronic, mechanical and chemical engineering, robust control is typically accomplished through the use of 'Integral Feedback Control', which is an effective strategy to guarantee robustness to step-like perturbations and uncertainties. This requires an integrator. In a nutshell, the integrator accumulates information about the system's past behaviour and uses it to adjust and improve its activity as more information becomes available. Integral Feedback Control allows, for example, cruise control systems to maintain a car at constant speed irrespective of the slope of the road or the combined weight of the passengers; or the speed of an escalator to remain constant regardless of the number of people using it. In this project, we will design, model, construct and test a biological integrator to implement 'in-vivo robust control'.

A fully (re-)programmable and controllable cell is one of the core long-term objectives of the blossoming field of synthetic biology. However, no biological integrator currently exists. To fill this gap, we will engineer the first in vivo 'plug-and-play' bio-integrator device that can be customised for different applications. To demonstrate the functionality of our bio-integrator device, we will use it to create engineered cells that can robustly maintain the concentration of a chosen small molecule around a specified value. To accomplish this, the cell will be equipped with both the ability to sense the extracellular concentration of the molecule and to synthesise and secrete the molecule itself. A rigorous control design will allow for the secretion rate to change dynamically so as to counteract step-like perturbations in the extracellular concentration of the molecule. This will establish the necessary theoretical and experimental basis for future extension of this research into in vivo environments.

For example, a biological integrator device would make it possible to engineer microbes that reside symbiotically with or within other organisms, and that are able to sense and self-adjust to changing and uncertain external conditions. We anticipate that this in turn could lead to the emergence of a revolutionary new form of medicine that we are calling 'active in vivo medicine', i.e. cells that are implanted in patients and monitor the concentration of disease-related biomolecules (e.g. insulin), modulating their production of these molecules in response to patient need.

In order to investigate how active in vivo medicine might be implemented in real-world conditions, we have integrated into this project a programme of work on 'Responsible Research and Innovation' designed to incorporate the perspectives of a wide range of interested parties into any future development of active in vivo medicine, including: biomedical researchers, clinicians, patient groups, regulators, pharmaceutical firms, and bioethicists.

Publications

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Related Projects

Project Reference Relationship Related To Start End Award Value
EP/K020781/1 21/05/2013 31/12/2015 £33,880
EP/K020781/2 Transfer EP/K020781/1 01/01/2016 31/05/2016 £14,621
 
Description Workshop on the Prospects for Controllable Cell-Based Therapies 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Workshop on the prospects for controllable cell-based therapies

Organised by
Claire Marris, Sociology Department, City University London
Guy-Bart Stan, CSynBI, Department of Bioengineering, Imperial College London
Karen Polizzi, CSynBI, Department of Life Sciences, Imperial College London
Jordan Ang, CSynBI, Department of Bioengineering, Imperial College London
feedback control for robust synthetic biology' (grants EP/K020781/1 and EP/K020617/1)
This workshop brought together diverse stakeholders to discuss the prospects for an emerging category of medical applications of synthetic biology that we are calling 'controllable cell-based therapies' (CCBTs) including:
• scientists conducting cutting-edge research to enable CCBTs
• firms seeking to commercialise CCBTs
• staff from agencies involved in the regulation of CCBTs
• independent experts on regulatory frameworks and translation for CCBTs
• staff from patient advocacy groups with expertise in medical innovation and regulation
• social scientists with expertise in medical innovation and regulation
The workshop provided a unique opportunity for people from these diverse groups to engage with each other in order to identify potential opportunities and challenges for this novel set of medical applications. Questions that were addressed at the workshop included:
• What is the current scientific, economic and regulatory landscape for CCBTs?
• How do CCBTs compare to alternative approaches to health and medicine?
• How can we ensure that these new therapies reach the clinic and provide actual benefits to patients without generating unreasonable risks?
• What implications might the use of bacterial (as opposed to human) cells have in terms of safety, regulatory frameworks and other challenges for translation to the clinic?
This workshop sought to encourage interactive discussions among people with different expertise and interests. Emphasis was given to group discussion, focused around case-studies. A small number of short presentations from experts from different disciplines helped set the scene and provide participants with basic information about: current cutting-edge science, ongoing commercial developments, regulatory frameworks, Health Technology Assessment, patient perspectives and consumer perspectives. The total number of participants was relatively small (25) in order to facilitate constructive discussions. The Chatham House rule applied whereby "participants are free to use the information received, but neither the identity nor the affiliation of the speaker(s), nor that of any other participant, may be revealed."
Year(s) Of Engagement Activity 2016
URL http://www.bg.ic.ac.uk/research/g.stan/group/CCBT_Workshop/CCBT_Workshop.html