About the Project
In the UK, around 10 million people suffer from chronic respiratory conditions, including asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). According to the British Lung Foundation, this amounts to >6 million inpatient bed days and lung diseases related deaths every 5 minutes.
This is a source of great fiscal burden on the NHS and the UK economy as well as emotional toll on the people whose lives are touched by these diseases. While treatment options exist, they do not target the pathological mechanisms. Furthermore, there is a general lack of cost-effective treatment decision-making. To target them, we need to understand how biological events integrating at gene, tissue, and environment levels regulate pathogenesis1. This systems level understanding will allow us to isolate key pathological events unique to a person’s genomic profile. This remains largely unexplored in respiratory medicine.
Dr Himanshu Kaul has recently been awarded a Research Fellowship by the Royal Academy of Engineering to develop an in silico lung that will capture personalised lung physiology and pharmacology. Towards this end, Dr Kaul aims to develop multiscale mathematical models capturing the systems-level impact of interactions at each decision-making hierarchical level (sub-cellular, cellular, etc.). The virtual asthma patient2,3, which captures interactions between multiple cell types, represents the ideal computational approach that the group will use to generate testable hypotheses. However, such models require robust validation of the outcome of interactions at each decision-making hierarchical level.
This PhD project will develop a protocol to culture multi-modular airway organoids and validate its relevance to in vivo physiology. Organoids4 are high-throughput 3D in vitro cultures with lower parametric complexity than animal models but reflect human physiology more closely. Airway organoids capture structural components (epithelium & mesenchyme) and markers of human airways robustly5. As such, they are ideal to investigate the nature of interactions between the cell types and the stimuli responsible for the emergence of pathology (e.g. organoids recapitulating cystic fibrosis6).
Airway organoids lack inflammatory cells and are yet to be co-cultured with them. The foundational hypothesis of this project is that multi-modular airway organoids created by co-culturing epithelial, mesenchymal, and inflammatory cells will recapitulate aspects of asthma pathophysiology. The rationale is that developing these organoids will enable us to control and manipulate biological interactions across multiple scales of space and time thus allowing us to identify systems-level insights into asthma, especially shared mechanisms between different asthma phenotypes.
Aims & Objectives
1. Develop protocol to culture multi-modular airway organoids
2. Optimise the protocol to ensure reproducibility and robustness
3. Validate the relevance of these organoids to human airways
Experimental plan and techniques
Validation that these organoids represent the in vivo physiology will occur via high-content imaging, flow cytometry, and bulk sequencing. The student will also compare the performance of organoids created using parental cell line vs gene edited cells (overexpressing genes such as IL33, etc). This comparison will help track the systems-level changes to the precise edits made at the genomic level. Supercomputers will be used to generate mechanistic hypotheses that will be tested via these multi-modular organoids to further validate their physiological relevance. The project is in collaboration with the School of Engineering.
A UK Bachelor’s Degree 2:1 or above or Overseas equivalent. You will be highly self-motivated and able to work well in a goal-oriented environment. You will have a background in Life Sciences, Biomedical Engineering, Respiratory Sciences, or a related field, and a rigorous approach to research, together with disciplined work habits and ability to organise own workload under supervision. You will possess excellent verbal and written communication skills. Training will be provided in mammalian cell culture, confocal imaging, and flow cytometry. Previous experience in any or all of these would be beneficial but is not essential.
2. Saunders R, Kaul H, Berair R, et al. 2019. Science Translational Medicine. DOI: 10.1126/scitranslmed.aao6451
3. Chachi L, Diver S, Kaul H, et al. 2019. European Respiratory Journal. DOI: 10.1183/13993003.00930-2019
4. Schutgens F and Clevers H. 2020. Annual Review of Pathology. https://doi.org/10.1146/annurev-pathmechdis-012419-032611
5. Tan Q et al. 2017. Biomaterials. doi: 10.1016/j.biomaterials.2016.10.046
6. Sachs N et al. 2019. EMBO Journal. https://doi.org/10.15252/embj.2018100300
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