Errors, like straws, upon the surface flow; He who would search for pearls must dive below.

John Dryden, All for Love

It is time for a cold shower. Reader, the author of this book has been misleading you. He has repeatedly used the word 'simple' and burbled on about the surprising simplicity at the heart of genetics. A gene is just a sentence of prose written in a very simple language, he says, preening himself at the metaphor. Such a simple gene on chromosome 3 is the cause, when broken, of alkaptonuria. Another gene on chromosome 4 is the cause, when elongated, of Hunting-ton's chorea. You either have mutations, in which case you get these genetic diseases, or you don't. No need for waffle, statistics or fudge. It is a digital world, this genetics stuff, all particulate inheritance. Your peas are either wrinkled or they are smooth.

You have been misled. The world is not like that. It is a world of greys, of nuances, of qualifiers, of 'it depends'. Mendelian genetics is no more relevant to understanding heredity in the real world than Euclidean geometry is to understanding the shape of an oak tree.

Unless you are unlucky enough to have a rare and serious genetic condition, and most of us do not, the impact of genes upon our lives is a gradual, partial, blended sort of thing. You are not tall or dwarf, like Mendel's pea plants, you are somewhere in between. You are not wrinkled or smooth, but somewhere in between. This comes as no great surprise, because just as we know it is unhelpful to think of water as a lot of little billiard balls called atoms, so it is unhelpful to think of bodies as the products of single, discrete genes. We know in our folk wisdom that genes are messy. There is a hint of your father's looks in your face, but it blends with a hint of your mother's looks, too, and yet is not the same as your sister's - there is something unique about your own looks.

Welcome to pleiotropy and pluralism. Your looks are affected not by a single 'looks' gene, but by lots of them, and by non-genetic factors as well, fashion and free will prominently among them. Chromosome 5 is a good place to start muddying the genetic waters by trying to build a picture that is a little more complicated, a little more subtle and a little more grey than I have painted so far. But I shall not stray too far into this territory yet. I must take things one step at a time, so I will still talk about a disease, though not a very clear-cut one and certainly not a 'genetic' one. Chromosome 5 is the home of several of the leading candidates for the tide of the 'asthma gene'. But everything about them screams out pleiotropy — a technical term for multiple effects of multiple genes. Asthma has proved impossible to pin down in the genes. It is maddeningly resistant to being simplified. It remains all things to all people. Almost everybody gets it or some other kind of allergy at some stage in their life. You can support almost any theory about how or why they do so. And there is plenty of room for allowing your political viewpoint to influence your scientific opinion. Those fighting pollution are keen to blame pollution for the increase in asthma. Those who think we have gone soft attribute asthma to central heating and fitted carpets. Those who mistrust compulsory education can lay the blame for asthma at the feet of playground colds. Those who don't like washing their hands can blame excessive hygiene. Asthma, in other words, is much more like real life.

Asthma, moreover, is the tip of an iceberg of 'atopy'. Most asthmatics are also allergic to something. Asthma, eczema, allergy and anaphylaxis are all part of the same syndrome, caused by the same 'mast' cells in the body, alerted and triggered by the same immunoglobulin-E molecules. One person in ten has some form of allergy, the consequences in different people ranging from the mild inconvenience of a bout of hay fever to the sudden and fatal collapse of the whole body caused by a bee sting or a peanut. Whatever factor is invoked to explain the increase in asthma must also be capable of explaining other outbreaks of atopy. In children with a serious allergy to peanuts, if the allergy fades in later life then they are less likely to have asthma.

Yet just about every statement you care to make about asthma can be challenged, including the assertion that it is getting worse. One study asserts that asthma incidence has grown by sixty per cent in the last ten years and that asthma mortality has trebled. Peanut allergy is up by seventy per cent in ten years. Another study, published just a few months later, asserts with equal confidence that the increase is illusory. People are more aware of asthma, more ready to go to the doctor with mild cases, more prepared to define as asthma something that would once have been called a cold. In the 1870s, Armand Trousseau included a chapter on asthma in his Clinique Medicale. He described two twin brothers whose asthma was bad in Marseilles and other places but who were cured as soon as they went to Toulon. Trousseau thought this very strange. His emphasis hardly suggests a rare disease. Still, the balance of probability is that asthma and allergy are getting worse and that the cause is, in a word, pollution.

But what kind of pollution? Most of us inhale far less smoke than our ancestors, with their wood fires and poor chimneys, would have done. So it seems unlikely that general smoke can have caused the recent increase. Some modern, synthetic chemicals can cause dramatic and dangerous attacks of asthma. Transported about the countryside in tankers, used in the manufacture of plastics and leaked into the air we breathe, chemicals such as isocyanates, trimellitic anhydride and phthalic anhydride are a new form of pollution and a possible cause of asthma. When one such tanker spilled its load of isocyanate in America it turned the policeman who directed traffic around the wreck into an acute and desperate asthmatic for the remainder of his life. Yet there is a difference between acute, concentrated exposure and the normal levels encountered in everyday life. So far there is no link between low-level exposure to such chemicals and asthma. Indeed, asthma appears in communities that never encounter them. Occupational asthma can be triggered in people who work in much more low-tech, old-fashioned professions, such as grooms, coffee roasters, hairdressers or metal grinders. There are more than 250 defined causes of occupational asthma. By far the commonest asthma trigger — which accounts for about half of all cases - is the droppings of the humble dust mite, a creature that likes our fondness for central-heated indoor winter stuffiness and makes its home inside our carpets and bedding.

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 alkapto-nuria 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 11, 13 and 14. This does not even count the fact that two parts of immunoglobulin E, the molecule at the centre of the process, are made by two genes on chromosome 1. The genetics of asthma could be underwritten by all of these genes in varying orders of importance or by any combination of them and others, too.

Each gene has its champion and feelings run high. William Cook-son, an Oxford geneticist, has described how his rivals reacted to his discovery of a link between asthma-susceptibility and a marker on chromosome 11. Some were congratulatory. Others rushed into print contradicting him, usually with flawed or small sample sizes. One wrote haughty editorials in medical journals mocking his 'logical disjunctions' and 'Oxfordshire genes'. One or two turned vitriolic in their public criticism and one anonymously accused him of fraud. (To the outside world the sheer nastiness of scientific feuds often comes as something of a surprise; politics, by contrast, is a relatively polite affair.) Things were not improved by a sensational story exaggerating Cookson's discovery in a Sunday newspaper, followed by a television programme attacking the newspaper story and a complaint to the broadcasting regulator by the newspaper. 'After four years of constant scepticism and disbelief, says Cookson mildly,2 'we were all feeling very tired.'

This is the reality of gene hunting. There is a tendency among ivory-towered moral philosophers to disparage such scientists as gold-diggers seeking fame and fortune. The whole notion of 'genes for' such things as alcoholism and schizophrenia has been mocked, because such claims have often been later retracted. The retraction is taken not as evidence against that genetic link but as a condemnation of the whole practice of seeking genetic links. And the critics have a point. The simplistic headlines of the press can be very misleading. Yet anybody who gets evidence of a link between a disease and a gene has a duty to publish it. If it proves an illusion, little harm is done. Arguably, more damage has been done by false negatives (true genes that have been prematurely ruled out on inadequate data) than by false positives (suspicions of a link that later prove unfounded).

Cookson and his colleagues eventually got their gene and pinned down a mutation within it that the asthmatics in their sample had more often than others did. It was an asthma gene of sorts. But it only accounted for fifteen per cent of the explanation of asthma and it has proved remarkably hard to replicate the finding in other subjects, a maddening feature of asthma-gene hunting that has recurred with distressing frequency. By 1994 one of Cookson's rivals, David Marsh, was suggesting a strong link between asthma and the gene for interleukin 4, on chromosome 5, based on a study of eleven Amish families. That, too, proved hard to replicate. By 1997 a group of Finns was comprehensively ruling out a connection between asthma and the same gene. That same year a study of a mixed-race population in America concluded that eleven chromosomal regions could be linked to susceptibility to asthma, of which ten were unique to only one racial or ethnic group. In other words, the gene that most defined susceptiblity to asthma in blacks was not the same gene that most defined susceptibility to asthma in whites, which was different again from the gene that most defined susceptibility to asthma in Hispanics.3

Gender differences are just as pronounced as racial ones. According to research by the American Lung Association, whereas ozone from petrol-burning cars triggers asthma in men, particulates from diesel engines are more likely to trigger asthma in women. As a rule, males seem to have an early bout of allergy and to outgrow it, while females develop allergies in their mid or late twenties and do not outgrow them (though rules have exceptions, of course, including the rule that rules have exceptions). This could explain something peculiar about asthma inheritance: people often appear to inherit it from allergic mothers, but rarely from their fathers. This could just mean that the father's asthma was long ago in his youth and has been largely forgotten.

The trouble seems to be that there are so many ways of altering the sensitivity of the body to asthma triggers, all along the chain of reactions that leads to the symptoms, that all sorts of genes can be 'asthma genes', yet no single one can explain more than a handful of cases. ADRB2, for example, lies on the long arm of chromosome 5. It is the recipe for a protein called the beta- 2-adrenergic receptor, which controls bronchodilation and bronchoconstriction - the actual, direct symptom of asthma in the tightening of the windpipe. The commonest anti-asthma drugs work by attacking this receptor. So surely a mutation in ADRB2 would be a prime 'asthma gene'? The gene was pinned down first in cells derived from the Chinese hamster: a fairly routine 1,239-letter long recipe of DNA. Sure enough a promising spelling difference between some severe nocturnal asthmatics and some non-nocturnal asthmatics soon emerged: letter number 46 was G instead of A. But the result was far from conclusive. Approximately eighty per cent of the nocturnal asthmatics had a G, while fifty-two per cent of the non-nocturnal asthmatics had G. The scientists suggested that this difference was sufficient to prevent the damping down of the allergic system that usually occurs at night.4

But nocturnal asthmatics are a small minority. To muddy the waters still further, the very same spelling difference has since been linked to a different asthmatic problem: resistance to asthma drugs. Those with the letter G at the same forty-sixth position in the same gene on both copies of chromosome 5 are more likely to find that their asthma drugs, such as formoterol, gradually become ineffective over a period of weeks or months than those with a letter A on both copies.

'More likely' . . . 'probably' ... 'in some of: this is hardly the language of determinism I used for Huntington's disease on chromosome 4. The A to G change at position 46 on the ADRB2 gene plainly has something to do with asthma susceptibility, but it cannot be called the 'asthma gene', nor used to explain why asthma strikes some people and not others. It is at best a tiny part of the tale, applicable in a small minority or having a small influence easily overridden by other factors. You had better get used to such indeterminacy. The more we delve into the genome the less fatalistic it will seem. Grey indeterminacy, variable causality and vague predisposition are the hallmarks of the system. This is not because what I said in previous chapters about simple, particulate inheritance is wrong, but because simplicity piled upon simplicity creates complexity. The genome is as complicated and indeterminate as ordinary life, because it is ordinary life. This should come as a relief. Simple determinism, whether of the genetic or environmental kind, is a depressing prospect for those with a fondness for free will.

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