The need for translational research in respiratory medicine

Lung diseases claim more lives now than they ever have. Chronic obstructive airways disease (COPD) will become the third leading cause of death according to predictions by the World Health Organization [1]. Lung carcinomas kill more people than any other cancers [2] and its increasing occurrence in non-smokers provokes further concerns. Medical advances over the past centuries have failed to eradicate lethal microbes such as tuberculosis [3], which was responsible for 1.4 million deaths in 2011 [4]. Pneumonia and pleural infection [5], once thought would extinct with advent of antibiotics, are also rising in incidences.

Advances in respiratory medicine are failing to meet the growing challenges from a diverse range of lung diseases [6]. More virulent and drug-resistant respiratory pathogens continue to emerge. Multi- (and even total-) drug resistant M. TB, penicillin-resistant pneumococci, methicillin-resistant Staphylococcus aureus, and carbapenem-resistant Enterobacteraciae are now commonplace. The massive global impact of SARS and H1N1 2009 influenza A have highlighted how vulnerable mankind remains in the ongoing war against our ever-evolving microbial enemies.

More than any other time in human history, we now need high quality, translatable, patient-focussed respiratory research - and fast! Resources for research are limited, and prioritization essential. Although ‘pure’ basic science is vital and major findings (e.g. discovery of the double helix) have profound implications, translational research to bring bench advances to the bedside is critical.

Success of translational research should be gauged by how (and how much) the result changes clinical practice. Meaningful translational research can only be achieved through close teamwork of scientists and clinicians at the frontline of clinical care.

The leap is massive from cell biology experiments performed under optimized laboratory conditions to successful outcomes in clinical trials which have to incorporate numerous inevitable (and uncontrollable) confounding factors inherent in human diseases. Animal models may be used to bridge the gap, but faithful models for human diseases are few and far between. All too often researchers overlook dissimilarities between their animal models and the human diseases under study, and such mistakes have been proven costly. When promising bench work fails to translate into clinical care, it sends years of hard work and millions of funding down the drain. The despair and frustration to the researchers are often beyond description.

Pneumonia research provides many such examples. Disease-modifying agents such as anti-tumor necrosis factor-alpha, granulocyte colony stimulating factor and tissue factor pathway inhibitor all performed splendidly in animal models but failed dismally in human clinical trials [7]. In the preclinical models used, pneumonia was induced acutely by intra-tracheal installation of large boluses of bacteria into animals. This is far removed from the slow onset of disease in humans which is often also modified by comorbidities of the host. It is no surprise that what works well in the mouse pneumonia model frequently does not work in man.

Another example is the mouse model of a single intra-tracheal instillation of bleomycin. For many years this model was used to examine disease pathogenesis and evaluate therapeutic targets for idiopathic pulmonary fibrosis (IPF), despite many differences in the anatomical distribution, disease chronicity and the level of acute lung inflammation between human IPF and bleomycin injured murine lungs. It is nowadays generally accepted that the bleomycin model is a better model for acute lung injury and not one of IPF [8].

These examples highlight the need for tight collaboration between bench and clinical researchers. Both must remain critical of existing models and be highly aware of the limitations of all in vitro and preclinical models employed.