Delineating late foetal human lung development and maturation

Our understanding of how the lung develops is very poor. Addressing this is really important because we can work out how to help premature babies and how to regenerate lungs to help those with severe lung disease. End-stage lung disease of any cause is a major global health problem. On the other hand, the death rate and problems arising from premature birth are mostly caused by the fact that the lung is too immature or underdeveloped to function as opposed to in healthy term babies. This is despite the use of some treatments such as steroids which do not overcome the long-term effects of premature birth on lung function as an adult.

I have already made important discoveries to understand lung development. This was made using human embryonic and foetal lungs up to 20 weeks post-conception - notably I have developed a 3D culture system which can be used to study human lung development in a dish. My work also includes how immune cells interact with the developing lung using various, cutting edge molecular methods that can look at each cell individually. The period of development after 20 weeks to birth is virtually unexplored and is referred to as the "gap" in the scientific world. In close collaboration with obstetricians and other doctors at UCL, I have designed a way of receiving fresh healthy tissue from any organ from this crucial period of development during the final part of pregnancy.

My aims will be 1) to study how the lining of the lung matures, 2) to study how the immune system matures within the lung and also elsewhere in our body, 3) to study how blood vessels mature and how they interact with the lung lining to make a functioning gas exchange unit, allowing oxygen to be transported into the blood compartment and carbon dioxide to be transferred into the air compartment, and finally 4) to set up a late foetal tissue resource for the other research groups working on the maturation of other organs.

My overall objective is to study late stage foetal human lung development and maturation, which has the potential for wide-reaching impact on various fields, most notably to improve survival in premature babies and to find ways to reverse the effects of severe lung disease.

End-stage lung disease is a major global health problem and understanding normal human lung development is an essential part of regenerative medicine. At the same time, the mortality and morbidity associated with prematurity is mostly caused by lung immaturity, despite the use of antenatal corticosteroids, which do not overcome the longterm effects of prematurity on lung function. I have made various important discoveries using human embryonic and foetal lungs up to 20 weeks post-conception - notably I have developed a genetically-modifiable organoid culture system which can be used to study human lung development in vitro. My work also includes developmental immunobiology in the lung using scRNAseq and novel approaches such as CITE-seq. The period of development after 20 weeks to birth is virtually unexplored and is referred to as the "gap". In close collaboration with obstetricians and histopathologists at UCL, I have designed a tractable way of receiving fresh healthy tissue from any organ from this crucial period of in utero development.

My aims are 1) to study late foetal epithelial maturation in the lung by scRNAseq, spatial transcriptomics and organoids in order to identify novel regulators in alveolar cell fate specification, 2) to study late foetal maturation of the immune system and whether the immune system in turn affects lung epithelial differentiation, 3) to study lung vascular maturation and the mechanism of endothelial-epithelial interactions to make a functioning gas exchange unit at the air-blood interface, and finally 4) to set up a late foetal tissue resource for the Human Cell Atlas, to facilitate functional work on other organs.

My overall objective is to delineate late foetal human lung development and maturation, which has the potential for wide-reaching impact on the whole field of lung developmental biology, lung regeneration and neonatal medicine.