Integrating living analytics into biomanufacturing processes

Cells are increasingly being used to manufacture a wide variety medicines, renewable plastics, chemicals, and other consumer products. Understanding the behaviour of cells during the manufacturing process is necessary to optimise production and to make sure that product yield and quality are high. Currently, this is done by measuring a few factors using established technologies based on chemistry. However, living systems have naturally have the ability to sense their environment and respond to changes accordingly. These mechanisms have better sensitivity and specificity than the chemical methods currently used. In the past few years, scientists have begun to harness these natural systems to develop analytical technology called biosensors. Biosensors can be used to detect the presence or absence of a molecule of interest in the environment. They also can be used to estimate the concentration of a molecule of interest (analyte). It is the latter type of biosensor that is interesting for biological manufacturing processes because it allows the accurate measurement of concentrations of key factors that are important for maximising the yield and productivity of cell-based manufacturing systems.

The aim of this proposal is to develop a framework for using living biosensors in biomanufacturing processes. The focus in on identifying the best way to grow the biosensor and the producing cell together in such away that both types of cells survive and function correctly. For this, we will try a number of different physical separation methods including membrane separation, trapping the biosensor in a polymer, or trapping the biosensor in a bubble of lipid. We will also try to genetically modify the biosensor cell to cause it to stick to the wall of the culture vessel or to bud off non-living particles that can still behave as biosensors, but can no longer grow.

Each of these strategies will be tested using a biosensor we have already developed to measure the concentration of an analyte coming from mammalian cells that are also producing a protein drug. We want to find conditions where the biosensor does not overgrow the mammalian cell, but still can sense and respond to changes in analyte concentration. Once the basic principle of a living analytic has been demonstrated, we hope that this will change the way that measurements of cellular behaviour are done in the future and lead to better understanding of cells during the manufacturing process. Hopefully one day this will lead to higher yields of products from biological manufacturing systems, which ultimately will decrease the costs to consumers.

Manufacturers in the bioprocessing industry will benefit from this research as it will open up a new methodology for analysis of cells during production. Living biosensors can sense a wider array of compounds that correlate with product yield and can detect analytes at extremely low concentrations giving them advantages over current technology. Engagement of both existing manufacturers and startups/SMEs in the synthetic biology space will allow the technology to be broadly adopted to have the most impact.

Adoption of this technology by industry will result in benefits to consumers of products made using biomanufacturing processes. Improved analytics will result in greater process understanding, allow manufacturers to develop processes with increased yields and product quality, driving down costs. In particular, in the recombinant protein therapeutic industry, the cost of these medicines to consumers is of concern as it places increased burden on the bodies that fund healthcare (e.g. the NHS). Therefore, measures that can improve productivity and decrease the costs of manufacturing would help to reduce the costs of these therapies and should also lead to increased access to a broader range of therapies (e.g. those currently considered too expensive).

Those engaging in synthetic biology and manufacturing research will benefit from the work as the first demonstration of the full potential of biosensors applied to bioprocessing. Synthetic biology has been discussed as a disruptive technology with the potential to change the way biological systems are engineered. Using synthetic biology to develop biosensors has already been demonstrated to have benefits, but the practical application of these to industrial processes has not yet been attempted. This project would be a tangible demonstration of the benefits of using synthetic biology in manufacturing in a creative and novel way. Thus, it could serve as a talking point for researchers to illustrate the benefits of synthetic biology for industrial applications.

Finally, the proposed project has potential for public engagement with research in manufacturing. The proposed project would lead to physical output such as new bioreactor probes that can be used to explain the concepts behind the research in a visual and attractive way. Thus, it could serve as a nice demonstration platform for public engagement activities at science fairs, festivals, or in school outreach activities.