Strategic Research Centre: Mucociliary clearance: from fundamentals to personalised medicine

Developing and apply pioneering new methods to study the mechanics of lung clearance, as a basis for developing effective and personalised therapeutic approaches for CF in the future.

Summary

Improving lung clearance would make a significant difference in the health and wellbeing of people with cystic fibrosis. However, the mechanics of how the lungs are cleared, and the impact of subtle differences in the cellular machinery used to do this are poorly understood. In this SRC, Professor Cicuta and colleagues will develop and apply pioneering new methods to study the mechanics of lung clearance, as a basis for developing effective and personalised therapeutic approaches in the future.

Background

Cells that line the lungs have an efficient system for keeping the lungs clear and infection-free. This involves tiny hairs on the surface of lung cells, called cilia, sweeping away liquid containing any trapped particles and bugs. The way that each cilia beats – the force of the beat, the angle they beat at and also whether they’re beating in time with their neighbours – makes a difference in how effectively they can clear particles and bugs from the lungs.

In a similar way, the properties of the mucus that the cilia are moving, for example how thick or thin the mucus is and how stretchy it is, will also impact the effectiveness of lung clearance. Until very recently, detailed methods to study how cilia beat and the properties of mucus were not possible. Professor Cicuta and his co-investigators on this SRC are pioneering new ways to study them.

Researchers have already identified several versions of some genes that control lung clearance, eg the way cilia beat, or the properties of mucus. In this SRC, researchers aim to find out how different versions of lung clearance genes affect what happens in cystic fibrosis. In the future this knowledge could give new insights into delivering personalised medicines.

Aims of the project

1. Clinical study to understand more about the genetic variation in lung clearance

From a list of lung clearance genes where one or more version of the gene has been found, the SRC team have chosen five genes to study in more detail in cystic fibrosis. The researchers will recruit people into a clinical study and compare which version of the gene each participant has with the severity of their symptoms, in order to understand the effect of these genetic variations on disease progression. They’ll also ask participants to donate samples for research, so the effect of these genetic variations on lung clearance can be studied in more detail in other parts of the programme.

2. Generation of genetically comparable lung cells for lab research

Everyone has hundreds of genetic variations, so when researchers want to study the effects of one specific genetic variation, all of the other variations can create ‘noise’ in the analysis and give misleading results. By using stem cells and gene-editing techniques, it is possible to make pairs of lung cells in the lab where the only difference between the pair is whether they have the rare or common version of the specific gene the researchers want to study. To create these types of cells in the lab is extremely time consuming and requires considerable technical expertise. 

3. Studying the movement of the cilia

Professor Cicuta’s lab at the Cavendish Laboratory of the University of Cambridge have expertise in studying cilia movement and co-ordination, and developing physics models to describe and predict them. They plan to model cilia movement and co-ordination in CF, and in particular to study the effects lung clearance genetic variations have on these movements. They will also develop an easier way of measuring and applying their models, creating a simple measurement usable by those not expert in this area.

4. Studying the properties of mucus in lung cells

In many cases, in order to understand the properties of a biological fluid, it is necessary to remove it from its natural surroundings and study it in artificial conditions in the lab. In doing this, allowances have to be made for how the experimental set up itself affects the results. The goal is always to study biology in a way that makes the least change possible to how it works naturally in the body.

SRC co-investigator Professor Gerard Fuller is Professor of Chemical Engineering at Stanford University in the USA, and his lab has pioneered a new approach for measuring the properties of mucus, where the measurements can be made without disturbing how the cells are growing. This is the most realistic way to date of studying the properties of mucus and it will be used in this SRC to understand what’s happening in cystic fibrosis.

Who is involved?

Principal investigator: Professor Pietro Cicuta, University of Cambridge

Co-investigators:

• Professor Ludovic Vallier, Cambridge Stem Cell Institute, University of Cambridge
• Dr Scott Randell, Marsico Lung Institute, University of North Carolina, Chapel Hill, USA
• Dr Charles Haworth, Royal Papworth Hospital, Cambridge
• Professor Gerald Fuller, School of Engineering, Stanford University, California, USA
• Professor Andres Floto, University of Cambridge