Mammalian Engineering Biology
Synthetic biology is being applied to gain insight into human health and disease and to transform medicine and healthcare.
Research in this area has been centred around the UK Centre for Mammalian Synthetic Biology, one of six multidisciplinary synthetic biology research centres in the UK. This was funded in 2014 by the BBSRC, EPSRC and MRC and the UK Research Council's Synthetic Biology for Growth Programme. The vision for the Centre was to develop the tools and technologies for mammalian synthetic biology, thereby enabling deeper insights into the fundamentals of mammalian biology and novel applications in biotechnology and biomedicine.
A 2022 transition award in Engineering Biology for Cell and Gene Therapy Applications derives from and builds upon this investment. Cell therapy and gene therapies (CGTs) are transforming biomedical research and medicine, with remarkable successes in recent years in prevention, or potentially cure, for both genetic and acquired diseases and injury.
Cell therapy (‘living medicines’) aims to treat disease by restoring or altering sets of cells, or by using cells as a delivery vehicle for genetically encoded therapies through the body. In cell therapy, cells are cultured or modified ex vivo, before being delivered to a patient via injection or implantation.
Gene therapy aims to treat diseases by replacing, inactivating or introducing genetically encoded factors into cells. Some therapies can combine both cell and gene therapies.
Cell and gene therapies will be transformed by the emerging tools and concepts of ‘Engineering Biology’.
We will create new engineering biology tools, and solutions for the known bottlenecks in the production of CGTs and enable new, inexpensive and safe therapies for future clinical applications.
We have expertise in tools for cell engineering, whole-cell modelling, DNA assembly and high-throughput screening to enable synthetic biology in mammalian systems.
The combination of the Edinburgh Genome Foundry’s huge capacity to build genetic constructs with the capabilities for high throughput phenotyping and selection capabilities (Berkeley Lights Beacon System – the only one in academia in Europe) provides an opportunity to rapidly perform the design, build, test learn Engineering Biology cycle in mammalian cells.
We are advancing basic understanding of mammalian biology while generating tools and technologies for near-term commercial exploitation. This work is underpinned by the exploration of responsible research and innovation, the development of standards, and how engagement with the public can inform design.
Our work benefits medicine and healthcare through innovation for the production of biologics, vaccine development, gene therapy, novel diagnostics and sensors, stem cell engineering and regenerative medicine.
New light-based systems turns off protein production
A collaboration between the UK Centre for Mammalian Synthetic Biology (Prof Jamie Davies and Dr Elise Cachat) and groups based in Germany, has harnessed optogenetics – light controlled switches of gene expression – to switch off protein production.
Most researchers study what a protein does in a cell by artificially manipulating its production. Many use chemicals to control the process but these can be toxic and have unexpected side effects.
Optogenetics offers a solution. Researchers build light-sensitive detectors into the molecular controllers of protein production and then trigger these with a beam of light. The technique can target cells with higher accuracy then chemicals and works in both cell cultures and in living animals. However, it has proven very difficult to create optogenetic systems that turn off protein production.
To address this, the team built a two-component, blue light-responsive optogenetic OFF switch (‘Blue-OFF’), which quickly reduces how much protein is made when illuminated. They combined a light responsive unit (KRAB-EL222), which halts protein production on illumination, with a module (B-LID) that marks proteins for degradation. So blue light targeted both gene expression and protein stability creating a fast and powerful response.
The researchers then showed that they could use the system to control cell death in a culture of human cells. This exciting new approach opens up novel perspectives in fundamental research and applications such as tissue engineering.
Stem cell hope for Parkinson’s Disease
A team of scientists, including Dr Tilo Kunath from the UK Centre for Mammalian Synthetic Biology, have taken a key step towards improving an emerging class of treatments for Parkinson’s disease.
Tilo and his team have created stem cells – which have the ability to transform into any cell type – that are resistant to developing Parkinson’s. They snipped out sections of DNA from human cells in the lab using advanced technology known as CRISPR. In doing so, they removed a gene linked to the formation of toxic clumps, known as Lewy bodies, which are typical of Parkinson’s brain cells.
In lab tests, the stem cells were transformed into brain cells that produce dopamine – a key brain chemical that is lost in Parkinson’s – in a dish. The cells were then treated with a chemical agent to induce Lewy bodies. Cells that had been gene-edited did not form the toxic clumps, compared with unedited cells, which developed signs of Parkinson’s.
The advance could be most beneficial to younger patients living with Parkinson’s and those with an aggressive form of the condition, but that the advance had to be tested in human trials. We know that Parkinson’s disease spreads from neuron-neuron, invading healthy cells. This could essentially put a shelf life on the potential of cell replacement therapy. Our exciting discovery has the potential to considerably improve these emerging treatments.
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