Asthma is on the rise. This complex condition currently affects more than 300 million people globally, with a further 100 million people likely to have asthma by 2025. Around 250,000 people die every year from the disease, which has no cure. Medication for asthma can only control the symptoms – to reduce the likelihood of future attacks and relieve future symptoms.
The characteristic symptoms of asthma include laboured breathing, cough and wheeze. The disease has no single cause and it varies between individuals. Whilst there is an inheritable element to asthma, this is not straightforward as more than 100 genes are associated with asthma. In addition to this genetic complexity, asthma also has an environmental component. The cold, smoke, paint fumes, even laughing can trigger attacks in people.
Much of the research into asthma uses an animal-based approach to mimic this human condition. Laboratory animal models of asthma tend to be mice, rats, rabbits, guinea pigs and macaques. However, these animals do not have asthma and so they need to be chronically manipulated to produce a ‘model’ that nevertheless does not develop the same disease as people with asthma. If the aim of research using animals is to generate the same symptoms- the wheeze, the cough, the breathlessness- as people with asthma, then what is the point in using these animals?
Unsurprisingly, mice and humans have very different airways, with different kinds of cells and unique anatomies. Therefore, key features of human asthma cannot be recreated in mouse models. In the lab, rats can be preferred over mice because some genetic strains of rat display the typical early and late stages of asthma attacks that people may experience. However, rats are often sensitised with injections into their bellies, followed by multiple ‘intranasal challenges’ (where they are subjected to the allergen, forcibly squirted up their noses daily, for extended periods). People with asthma do not have their trigger injected into their stomach. Guinea pigs are a so-called ‘good model’; these animals are ‘sensitised’ by enforced inhalation of irritants, such as the complex protein ovalbumin – found in egg whites – or toxic chemicals such as toluene diisocyanate. The latter produces an inflammatory response that ultimately results in damage to their lungs; yet these irritants are not associated with the human condition.
And what about macaques? The rationale for using these animals has nothing to do with the science or the disease mechanisms or the likely success of possible treatments. Macaques have similar genetics and anatomy to people and their large size, compared to mice, allows functional analysis of the airways that is not possible in rodents. However, macaques do not develop asthma naturally and so they have to be subjected to an intense and unnatural sensitising process in order to generate features of asthma.
Researchers developed the first primate model of asthma in 1968 and these are still used today. Just two years ago, researchers published a study that reportedly took 48 baby rhesus monkeys from their mothers when they were two days old. These babies, ripped from their family groups, were housed in ’exposure chambers’, injected in the back with an allergen and forced to inhale various different chemical challenges to give them airways disease. This was repeated thirty three times over six months, until 24 of the baby macaques were killed and the remaining 24 animals were allowed to ‘recover’ for three years before they too were killed and their organs removed for analysis.
In my opinion, we can learn more from human-focused and human-relevant research. The complexity and diversity of human asthma produces a spectrum of symptoms and responses to treatments that differ for individuals. Instead of genetically manipulated mice to try and generate symptoms of asthma, we can analyse people with asthma to see which genes are different and how that impacts on their ability to respond to potential treatments. Instead of taking baby macaques away from their families, we can use complex cell culture in the laboratory. These experiments aim to recreate the human airways to reveal how they respond to foreign bodies.
The most powerful tool in the fight to cure asthma is likely to be the people with asthma- studies on volunteers with asthma can provide vital information on likely triggers and responses to drugs. It is painless and straightforward to harvest cells from the airways of people with asthma. These cells retain the features of the disease and can be grown in the laboratory. It is important to note that studies have shown that the cell culture models responded differently, depending on the severity of asthma of the person who originally donated the cells, in the same way that people with asthma may respond differently to potential asthma triggers or new medication.
More recently, an intricate model of an ‘asthmatic lung on a chip’ has been shown to react to drug treatment in a remarkably similar manner to a person with asthma. In this model, corticosteroid application had no effects, in line with many people with asthma who fail to respond to steroids, but a different drug, currently used for rheumatoid arthritis, reversed the asthma-like characteristics of the model. The potential for these accurate and relevant human models to investigate drug repurposing, without the need for any further animal studies, is huge.
Image courtesy of theguardian.com
There are also likely advances to be made in developing new drugs. Many of these new drugs fail, after apparently successful trials in animals, when they reach clinical trials, where they are tested in patient groups for the first time. For asthma, this may be due to lack of efficacy (the drugs didn’t work) or because the drugs did not ‘behave’ as expected. Putting these drugs into a human lung on a chip system would allow investigators to examine where the drug went (what cells does it attach to), how long the drugs last and whether it reduces those features of asthma that we have seen recreated in the models.
Through this human-centred research, we have learned which pathways are involved in the asthmatic responses and how to block these to better relieve symptoms. We can then measure how new drugs affect people with asthma and identify markers of improved, or failing, lung function. Altogether, these human approaches offer a more personalised and relevant way to examine this human condition than baby monkeys taken away from their mothers.