Building next generation growth factors for organoid-driven precision medicine: a protein engineering project co-funded by Innovate UK

We were delighted to be awarded Innovate UK funding in the precision medicine call to address issues of quality and availability of cytokines and growth factors for use in organoid technologies.  In a project that started in December 2017, the Qkine R&D team are applying a combination of protein expression, refolding optimisation and structure-guided protein engineering to improve the biological properties and quality of proteins such as R-spondins, TGFβ1, members of the BMP family and their inhibitors Noggin and Gremlin, and key FGF family proteins.

One of the most exciting innovations in precision medicine is the use of organoids – miniature three-dimensional structures made of self-assembling groups of cells that mimic organs such as the gut, liver, pancreas or brain ^1–4, or in the case of cancer organoids, tumours ^5,6.  Crucially, these organoids retain the genetic information from the person who donated the original tissue biopsy, allowing researchers to connect genomic information with a living model of the biological responses of that individual to drugs and environmental factors. However, growing these tiny disease models requires a precise cocktail of proteins, or growth factors, that help model the microenvironment within the body.  These proteins are hard to make and expensive, and their use is often limited by variable quality and commercial availability.

In this project, co-funded by the UK’s innovation agency, Innovate UK, we are busy tackling some of these challenges. Initially, we are focusing on proteins used during the growth of human cancer organoids, which offer opportunities to improve drug discovery and treatment, and intestinal organoids that provide a model system to advance understanding of important medical conditions including inflammatory bowel disease.

Now, almost halfway through the project, product development is going well and two new high purity proteins have been produced and made available for pre-release testing.

Commenting on progress so far, Qkine’s scientific founder Marko Hyvönen said: “We have made good progress in developing methods for making high-purity FGF4 and FGF10, two of the key targets in this project, and these proteins have been sent to collaborators in the organoid field for testing.  TGFβ1, an important growth factor for the research community, is proving more challenging to make at high quality; the Innovate UK support is enabling us to develop a range of protein engineering techniques to address this.”

About Innovate UK

Innovate UK is the UK’s innovation agency. It works with people, companies and partner organisations to find and drive the science and technology innovations that will grow the UK economy. For further information visit www.innovateuk.gov.uk

References

1. Broutier, L. et al. Human primary liver cancer–derived organoid cultures for disease modeling and drug screening. Nat. Med. 23, 1424–1435 (2017).
2. Lancaster, M. A. et al. Guided self-organization and cortical plate formation in human brain organoids. Nat. Biotechnol. 35, 659–666 (2017).
3. Noben, M. et al. Human intestinal epithelium in a dish: Current models for research into gastrointestinal pathophysiology. United Eur. Gastroenterol. J. 5, 1073–1081 (2017).
4. Devarasetty, M., Mazzocchi, A. R. & Skardal, A. Applications of Bioengineered 3D Tissue and Tumor Organoids in Drug Development and Precision Medicine: Current and Future. BioDrugs 32, 53–68 (2018).
5. Drost, J. & Clevers, H. Organoids in cancer research. Nat. Rev. Cancer (2018). doi:10.1038/s41568-018-0007-6
6. Francies, H. E. & Garnett, M. J. What role could organoids play in the personalization of cancer treatment? Pharmacogenomics 16, 1523–1526 (2015).