FRAME Annual Lecture 2010
At the FRAME Lecture, "Alternative Experimental Models for Lung Research: stuck between a rat and a hard place", Dr Kelly BéruBé explained research into the use of in vitro models of human lung tissue that has enabled her team to identify pathways by which air pollutants cause lung injury such as inflammation, which can lead to worsened symptoms in people with pre-existing lung and heart diseases.
The model is extremely important to the Three Rs because it replaces the use of rats, but it also has the advantages of being inexpensive, user-friendly and more reliable than animal experiments.
The team has used the “micro-lungs” to test a range of potentially hazardous particulate substances that are found in the ambient atmosphere and found commonality in the way that they cause lung damage. It has also been possible to identify which variables, such as particle size and chemistry, that increases the likelihood of damage occurring.
She said the model would provide a useful way for testing new drugs that could help prevent or repair damage caused by smoking or industrial pollution. The model uses medical waste tissues donated from lung patients and involves re-growing isolated stem cells on an artificial scaffold that mimics the natural matrix that supports the human lung.
The 3-dimensional construct forms multiple-layers with differentiated cells that replicate the different cell types and functions of the lung airway tissues in a living body. The in vitro model allows visualisation by all forms of microscopy, and in conjunction with immuno-histochemistry, permits identification of biomarkers of exposure and harm to test substances.
Intelligent biomarker discovery can be used for candidate drug efficacy and safety, as well as clinical and therapeutic interventions.She stressed the importance of the development by saying: “In fifteen years of rat experiments we have never identified the things that we have found in only five years of using a human-tissue model.”
The pharmaceutical industry is under increasing pressure to deliver products that meet prescribed claims, lack side-effects and perform accordingly despite a patient’s genetic background. To discover a new drug, many compounds must be screened and evaluated for efficacy and toxicity, and much of that testing occurs outside the species of interest, in animals or in their tissues. The ensuing extrapolation of results to humans is fraught with difficulty, especially given that individual people can react differently to the same drug. Researchers therefore require adequate systems that allow early elimination of poor drug candidates, permitting focus on more promising ones.
The recycling of human tissues from patient donors (live and post mortem) provides this system, without the need for surrogate animal models. In the specific case of respiratory medicine, lung tissues can now be recapitulated as tools for screening assays for inhalation toxicology, to predict efficacy/toxicity following exposure to drugs and pollutants. The development of human cell-based assays is required to investigate drug targeting to the lung to treat pulmonary disease; examine use of the lung as a portal for the systemic delivery of non-pulmonary drugs; and to target, for example, cancer in other organs.
Dr BéruBé is Director of the Lung and Particle Research Group at the School of Biosciences, University of Cardiff.
Lecture held November 4.