The list of asthma triggers given by the American Lung Association covers all walks of life: pollen, feathers, moulds, foods, colds, emotional stress, vigorous exercise, cold air, plastics, metal vapours, wood, car exhaust, cigarette smoke, paint, sprays, aspirin, heart drugs – even, in one kind of asthma, sleep. There is material here for anybody to grind any axe they wish. For instance, asthma is largely an urban problem, as proved by its sudden appearance in places becoming urban for the first time. Jimma, in south-west Ethiopia, is a small city that has sprung up in the last ten years. Its local asthma epidemic is ten years old. Yet the meaning of this fact is uncertain. Urban centres are generally more polluted with car exhaust and ozone, true, but they are also somewhat sanitised.
One theory holds that people who wash themselves as children, or encounter less mud in everyday life, are more likely to become asthmatics: that hygiene, not lack of it, is the problem. Children with elder siblings are less likely to get asthma, perhaps because their siblings bring dirt into the house. In a study of 14,000 children near Bristol, it emerged that those who washed their hands five times a day or more and bathed twice a day, stood a twenty-five per cent chance of having asthma, while those who washed less than three times a day and bathed every other day had slightly over half that risk of asthma. The theory goes that dirt contains bacteria, especially mycobacteria, which stimulate one part of the immune system, whereas routine vaccination stimulates a different part of the immune system. Since these two parts of the immune system (the Th1 cells and the Th2 cells respectively) normally inhibit each other, the modern, sanitised, disinfected and vaccinated child is bequeathed a hyperactive Th2 system, and the Th2 system is specially designed to flush parasites from the wall of the gut with a massive release of histamine. Hence hay fever, asthma and eczema. Our immune systems are set up in such a way that they ‘expect’ to be educated by soil mycobacteria early in childhood; when they are not, the result is an unbalanced system prone to allergy. In support of this theory, asthmatic attacks can be staved off in mice that have been made allergic to egg-white proteins by the simple remedy of forcing them to inhale mycobacteria. Among Japanese schoolchildren, all of whom receive the BCG inoculation against tuberculosis but only sixty per cent of whom become immune as a result, the immune ones are much less likely to develop allergies and asthma than the non-immune ones. This may imply that giving the Th1 cells some stimulation with a mycobacterial inoculation enables them to suppress the asthmatic effects of their Th2 colleagues. Throw away that bottle steriliser and seek out mycobacteria.1
Another, somewhat similar, theory holds that asthma is the unleashed frustration of the worm-fighting element in the immune system. Back in the rural Stone Age (or the Middle Ages, for that matter), the immunoglobulin-E system had its hands full fighting off roundworms, tapeworms, hookworms and flukes. It had no time for being precious about dust mites and cat hairs. Today, it is kept less busy and gets up to mischief instead. This theory rests on a slightly dubious assumption about the ways in which the body’s immune system works, but it has quite a lot of support. There is no dose of hay fever that a good tapeworm cannot cure, but then which would you rather have?
Another theory holds that the connection with urbanisation is actually a connection with prosperity. Wealthy people stay indoors, heat their houses and sleep on feather pillows infested with dust mites. Yet another theory is based on the undoubted fact that mild, casual-contact viruses (things like common colds) are increasingly common in societies with rapid transport and compulsory education. Schoolchildren harvest new viruses from the playground at an alarming rate, as every parent knows. When nobody travelled much, the supply of new viruses soon ran out, but today, with parents jetting off to foreign lands or meeting strangers at work all the time, there is an endless supply of new viruses to sample at the saliva-rich, germ-amplifying stations we call primary schools. Over 200 different kinds of virus can cause what is collectively known as the common cold. There is a definite connection between childhood infection with mild viruses, such as respiratory syncitial virus, and asthma susceptibility. The latest vogue theory is that a bacterial infection, which causes non-specific urethritis in women and has been getting commoner at roughly the same rate as asthma, may set up the immune system in such a way that it responds aggressively to allergens in later life. Take your pick. My favourite theory, for what it is worth, is the hygiene hypothesis, though I wouldn’t go to the stake for it. The one thing you cannot argue is that asthma is on the increase because ‘asthma genes’ are on the increase. The genes have not changed that quickly.
So why do so many scientists persist in emphasising that asthma is at least partly a ‘genetic disease’? What do they mean? Asthma is a constriction of the airways, which is triggered by histamines, which are in turn released by mast cells, whose transformation is triggered by their immunoglobulin-E proteins, whose activation is caused by the arrival of the very molecule to which they have been sensitised. It is, as biological chains of cause and effect go, a fairly simple concatenation of events. The multiplicity of causes is effected by the design of immunoglobulin E, a protein specially designed to come in many forms, any one of which can fit on to almost any outside molecule or allergen. Although one person’s asthma may be triggered by dust mites and another’s by coffee beans, the underlying mechanism is still the same: the activation of the immunoglobulin-E system.
Where there are simple chains of biochemical events, there are genes. Every protein in the chain is made by a gene, or, in the case of immunoglobulin E, two genes. Some people are born with, or develop, immunological hair-triggers, presumably because their genes are subtly different from those of other people, thanks to certain mutations.
That much is clear from the fact that asthma tends to run in families (a fact known, incidentally, to the twelfth-century Jewish sage of Cordoba, Maimonides). In some places, by accident of history, asthma mutations are unusually frequent. One such place is the isolated island of Tristan da Cunha, which must have been populated by descendants of an asthma-susceptible person. Despite a fine maritime climate, over twenty per cent of the inhabitants have overt symptoms of asthma. In 1997 a group of geneticists funded by a biotechnology company made the long sea voyage to the island and collected the blood of 270 of the 300 islanders to seek the mutations responsible.
Find those mutant genes and you have found the prime cause of the underlying mechnanism of asthma and with it all sorts of possibilities for a cure. Although hygiene or dust mites can explain why asthma is increasing on average, only differences in genes may explain why one person in a family gets asthma and another does not.
Except, of course, here for the first time we encounter the difficulty with words like ‘normal’ and ‘mutant’. In the case of alkaptonuria it is pretty obvious that one version of the gene is normal and the other one is ‘abnormal’. In the case of asthma, it is by no means so obvious. Back in the Stone Age, before feather pillows, an immune system that fired off at dust mites was no handicap, because dust mites were not a pressing problem in a temporary hunting camp on the savannah. And if that same immune system was especially good at killing gut worms, then the theoretical ‘asthmatic’ was normal and natural; it was the others who were the abnormals and ‘mutants’ since they had genes that made them more vulnerable to worm infestations. Those with sensitive immunoglobulin-E systems were probably more resistant to worm infestations than those without. One of the dawning realisations of recent decades is just how hard it is to define what is ‘normal’ and what is mutant.
In the late 1980s, off went various groups of scientists in confident pursuit of the ‘asthma gene’. By mid-1998 they had found not one, but fifteen. There were eight candidate genes on chromosome 5 alone, two each on chromosomes 6 and 12, and one on each of chromosomes