The Synthetic Biological Engineering of Self-Assembling Micro-Hearts for Cardiac Drug Testing
Lead Research Organisation:
University of Manchester
Department Name: Materials
Abstract
Pharmaceutical drug development is increasingly more expensive and time consuming due to the lack of effective laboratory tissue/disease models that accurately predict drug efficacy and safety. In this fellowship I will address this challenge by combining synthetic biology with tissue engineering. Focusing on cardiac drug testing, I will reprogram stem cells through synthetic biology to automatically self-assemble into small, 0.5-1 mm diameter spherical heart tissue constructs (i.e. micro-hearts). Synthetic biologically engineered micro-hearts satisfy all requirements of an effective cardiac drug testing tool, and are cheaper than currently used methodologies. As an effective and inexpensive drug testing tool it will help reduce the cost of drug development, helping the pharmaceutical industry, an £8.8 billion UK sector, survive and thrive. Cheaper and more effective cardiac drugs will lessen the £11 billion burden of cardiovascular diseases on the NHS, and improve the quality of life of the 7 million people living with these diseases today in the UK.
Planned Impact
Society: Patients with cardiac problems, patients in general
There are an estimated 7 million people living with cardiovascular disease in the UK. The proposed micro-heart technology will enable faster and cheaper drug development (both cardiac and other). A long term impact of this is more new, more effective and cheaper cardiac drugs.
Society: National Health Service
The healthcare cost of treating cardiovascular diseases is £11 billion each year in the UK. The impact of the micro-heart technology will be a significant reduction of developmental cost associated with cardiac drugs. Cardiac drugs will be cheaper, and therefore the burden on the NHS/patients lower.
Society: Animals in research
Animals are heavily used in cardiac safety/drug efficacy testing. In 2014 according to Home Office data collection statistics 62,778 basic research experimental procedures were carried out on living animals in the UK in cardiovascular studies. Micro-hearts will provide a cost-effective alternative to animal models, significantly reducing the number of animals in research.
Economy: Pharmaceutical industry, biotechnology SMEs
The pharmaceutical industry is the UK's top research sector, spending around £8.8 billion on UK research and development. The ever increasing cost of drug development is a major burden for the big biopharmaceuticals, but even more so for the small and medium-size enterprises working in this industry. Reduced drug development cost will help these businesses survive and thrive, creating a more diverse industry.
Economy: Pharmaceutical employees
The pharmaceutical industry employs around 26,000 people in the UK A further 250,000 people work in related industries. Cheaper drug development will permit a greater proportion of this work to be carried out in the UK without re-location to other countries, retaining and creating more jobs.
Knowledge: Tissue engineers
A completely new approach to engineering tissues. A solution to the challenge of multi-layered and graduated tissue engineering.
Knowledge: Tissue engineering, synthetic biology and mathematical modelling communities
The fellowship will form a bridge between the synthetic biology and tissue engineering communities. Similar connections will be formed with the mathematical modelling community. With effective communication these will engender new collaborations and grant proposals.
Knowledge: The public
Through the outreach activities I will undertake as part of this fellowship, I will disseminate information to the public on the potential of synthetic biology, from cleaning up toxic waste and producing new types of antibiotics, to cancer treatment, and address their safety concerns regarding genetic modification.
There are an estimated 7 million people living with cardiovascular disease in the UK. The proposed micro-heart technology will enable faster and cheaper drug development (both cardiac and other). A long term impact of this is more new, more effective and cheaper cardiac drugs.
Society: National Health Service
The healthcare cost of treating cardiovascular diseases is £11 billion each year in the UK. The impact of the micro-heart technology will be a significant reduction of developmental cost associated with cardiac drugs. Cardiac drugs will be cheaper, and therefore the burden on the NHS/patients lower.
Society: Animals in research
Animals are heavily used in cardiac safety/drug efficacy testing. In 2014 according to Home Office data collection statistics 62,778 basic research experimental procedures were carried out on living animals in the UK in cardiovascular studies. Micro-hearts will provide a cost-effective alternative to animal models, significantly reducing the number of animals in research.
Economy: Pharmaceutical industry, biotechnology SMEs
The pharmaceutical industry is the UK's top research sector, spending around £8.8 billion on UK research and development. The ever increasing cost of drug development is a major burden for the big biopharmaceuticals, but even more so for the small and medium-size enterprises working in this industry. Reduced drug development cost will help these businesses survive and thrive, creating a more diverse industry.
Economy: Pharmaceutical employees
The pharmaceutical industry employs around 26,000 people in the UK A further 250,000 people work in related industries. Cheaper drug development will permit a greater proportion of this work to be carried out in the UK without re-location to other countries, retaining and creating more jobs.
Knowledge: Tissue engineers
A completely new approach to engineering tissues. A solution to the challenge of multi-layered and graduated tissue engineering.
Knowledge: Tissue engineering, synthetic biology and mathematical modelling communities
The fellowship will form a bridge between the synthetic biology and tissue engineering communities. Similar connections will be formed with the mathematical modelling community. With effective communication these will engender new collaborations and grant proposals.
Knowledge: The public
Through the outreach activities I will undertake as part of this fellowship, I will disseminate information to the public on the potential of synthetic biology, from cleaning up toxic waste and producing new types of antibiotics, to cancer treatment, and address their safety concerns regarding genetic modification.
People |
ORCID iD |
| Richard Balint (Principal Investigator / Fellow) |
Publications
Tandon B
(2018)
Electroactive biomaterials: Vehicles for controlled delivery of therapeutic agents for drug delivery and tissue regeneration.
in Advanced drug delivery reviews
| Description | In mammalian synthetic biology the standardisation of parts does not exist. DNA sequences of the parts are also very difficult to obtain. For many of them alternative sequences exist. There is no clear information available on the effect of the differences between these alternative sequences, or how these part should be assembled for them to work in the desired manner. To overcome this I have assembled a database of mammalian synthetic biology parts/sequences with over 200 entries. The differences between alternative sequences of the same part have been analysed, and where information is available, the effect of these differences have been annotated to the sequence. This database will form part of a series of review articles - containing citable sequences for future mammalian synthetic biologists - that I hope will become a reference document for the field and engender the standardisation of parts. As of March 2021 four manuscripts have been prepared for the above review series and are ready for publication. . Beyond this I have standardised the construction of my plasmids, and have developed a system for the quick assembly of the large numbers of plasmids this project needs based on UNS sequences. This will make assembly not only quicker but significantly cheaper. Using this technique I have assembled a large set of plasmids (over 60). I have identified a way to generate stably transfected Mesenchymal Stem Cells with near 80% efficiency, something that is less than 1% efficient with standard plasmid-based methods. I have also optimised the methodology for selecting these stably transfected cells from mixed populations. The plasmids I have assembled were delivered to the stem cells and tested. Stable cell lines for testing the multilayered gene expression inside spheroids have been prepared and are ready for population purification. Due to the Covid pandemic the final set of experiments purifying and testing the stable cell populations could not be performed. |
| Exploitation Route | A database of reference sequences for the field. A series of review article describing these sequences with clear guidelines on how they should be assembled. Dr Balint has prepared a set of 4 manuscripts, ready for publication, containing the database. Another 2 or 3 manuscripts are also in progress. Through oral presentations at the international TERMIS 2019 and national TCES 2019 conferences, and poster presentations at the national TCES 2019 at the international mSBW 2019 conferences in the US my work has been disseminated and received a lot of interest. Especially, the methodology for efficient plasmid assembly and stable transfection into Mesenchymal Stem Cells I optimised is expected to be of great interest to colleagues in the field. |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
| Description | Manchester Synthetic Biology Research Centre SYMBIOCHEM Flexible Talent Mobility Account |
| Amount | £120,000 (GBP) |
| Funding ID | BB/S507957/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 11/2018 |
| End | 03/2021 |
| Description | Collaboration with Prof Ron Weiss from MIT |
| Organisation | Massachusetts Institute of Technology |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Funded by a BBSRC-FTMA2 Outgoing Innovation Fellowship I spent two months at MIT in the labs of Prof Ron Weiss. Prof Ron Weis is the world leading expert in mammalian synthetic biology (the focus of my fellowship). Our collaboration was aimed at exploring whether the cadherin technology championed in Prof Weiss' lab can be used with Mesenchymal Stem Cells (the focus of my fellowship) to form layered structured in spheroids. I designed the piggyBAC plasmids to be used with the human stem cells, and brought these to the MIT alongside with a set of reagents and consumables. I also contributed expertise in human stem cells and piggyBAC transfection. |
| Collaborator Contribution | This visit exposed me to a large set of novel technologies currently developed at MIT. They also provided me with their own plasmids and cell lines, and access to cutting edge equipment. Their expertise in cadherins and other novel synthetic biology technologies were a great boon for my personal development as an expert in my field. I also participated in weekly seminars in the Koch Institute and in a lecture by George Church, the famous geneticist, in the Harvard Medical School. |
| Impact | Collaboration is in its infancy and ongoing. |
| Start Year | 2019 |
| Description | Lecture to students in summer school |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | I gave an introductory lecture on tissue engineering to school students participating in the UoM Biomaterials Summer School. The students were at that stage where they are making decisions about their future careers. The hope is that we can encourage more of them to study tissue engineering, biomaterials, and STEM subjects in general. There was a lot of interest from the students after the talk. |
| Year(s) Of Engagement Activity | 2017 |