by Greg Gibson
You would think that hand washing and modern style latrines would have been more common among the affluent 50 years ago. Perhaps some other aspect of personal hygiene was at play here. We also know now that only a few percent of all polio infections are symptomatic at all. The vast majority of the tens of millions of people who had the virus in their bloodstream probably never knew about it and lived perfectly normal lives without paralysis or gastrointestinal problems. Is it possible that the less affluent rural black population was protected because they had a stronger and better balanced immune system as a result of their life circumstances?
Asthma Epidemiology
What are the environmental factors influencing asthma prevalence? The distribution of asthma is remarkably inverse to that of diabetes. In the United States, levels are twice as high in the Northeast, Midwest, and Northwest, as they are in Texas and Louisiana, and they are intermediate along the Atlantic coast. An anomaly is Puerto Rico, where 1 in 5 kids are asthmatic, even though Hispanics as an ethnic group tend to have a lower prevalence than Caucasian and African Americans.
This geographic trend is not, however, reflected in measures of education and affluence. In just about every state in the Union, high school graduates have lower rates of asthma than those who drop out, while college graduates have significantly lower rates again. Interestingly, almost everywhere, not finishing college is accompanied by a spike in asthma susceptibility. The exceptions? Quite strikingly, California, where increased education is correlated with more asthma, and to a lesser extent the arid southwest states where the socioeconomic differences are not so pronounced.
This suggests that there are multiple layers to the impact of the human lifestyle transition from agrarian to modern urban settings on asthma susceptibility. While there quite likely is an impact of improved hygiene resulting in failure to appropriately prime the complex immune system, this is to a great extent offset by exposure to irritants. Chief among these are particulates in the house, such as cockroach or house dust mite dander, and fumes in the air, such as cigarette smoke, the fumes emanating from our freeways, and the airborne legacy of the industrial way of life.
Globally a couple of other phenomena confirm that the hygiene hypothesis explains only a fraction of the prevalence. Six of the seven countries at greatest risk of both childhood and adult asthma are Anglo-Saxon derivatives: Great Britain, Australia, New Zealand, Canada, the United States, and Ireland. The seventh is Brazil, whose latitudinal neighbor Peru is right up there as well, despite the fact that Portugal and Spain are if anything on the low side among European countries. These aren’t just tendencies either; we’re talking about whopping great tenfold differences. So prevalent is asthma in Australia that the folk cure of draping a towel over your head and inhaling Vick’s Vaporub in boiling water inspired a scene in the movie Crocodile Dundee. Coming across a bleary-eyed man snorting cocaine, Paul Hogan intervened by dumping some of the white powder into a bowl of hot water and holding the unsuspecting partygoer’s head over the fumes. A quarter of all Anglo kids have asthma symptoms, five times the fraction elsewhere.
The good news is that the world’s most populous countries have the lowest asthma rates. China, India, Russia, Indonesia, and Mexico are well off in terms of incidence, though sadly they lead the world in terms of fatality rates among asthmatics. In fact, the fatality rate map is pretty much an inversion of the incidence one, with a disturbing exception. Among the afflicted nations, the United States lags notably in its ability to prevent fatalities. It doesn’t take an epidemiologist to recognize that this has a lot to do with access to preventative health care for the less well off.
Genetics of Asthma
On top of all this, asthma tends to run in families. Not as much as blonde hair and blue eyes, but certainly more than cancer or alcoholism. Inheritance is often a telltale sign of genetics, but the inheritance of asthma might have as much to do with families sharing musty homes as predisposing genes.
The only way to really see whether genes are involved is to find them and work out how they work. Scans for genes shared by affected family members have been performed often enough that half a dozen places in the genome keep coming up, and another dozen or so have appeared often enough to make us suspicious. The conclusion is that asthma, like diabetes, is a pretty good example of a disease influenced by a complex mixture of dozens of genetic variants. Unfortunately, we do not yet know the identities of the genes in those bits of chromosomes shared by asthmatic relatives. The genetic terrorists, as it were, have been tracked to a few neighborhoods, but door-to-door searches will be needed to find the actual culprits.
That it can be done is shown by the example of ADAM33. A team of investigators at the threateningly named Genome Therapeutics Corporation tracked down this gene in hundreds of British and North American families. Just what is different about the version that makes some people susceptible to asthma is not yet clear, nor is it obvious how many of us are at risk, because any number of the SNPs in the gene could be responsible. (Recall that SNPs are the subtle changes in DNA spelling at a single letter—single nucleotide polymorphisms—that are littered throughout our genomes.) Nor is it obvious that knowing which type you have will be of much use to anyone in any case, since the relative risk it confers is pretty small. Nor does it account for more than a minor fraction of all asthma.
What is interesting about ADAM33 is that it points our attention to quite a different aspect of the biology of problematic breathing than inflammation. This is because the gene encodes a pair of molecular scissors. Technically it is a zinc-dependent matrix metalloproteinase expressed in the bronchial smooth muscle and lung epithelium. Roughly translated, this means that it helps ensure that a person’s airways are flexible.
In asthmatics, chronic inflammation causes the airway walls to thicken, which as well as narrowing the passages through which the air gets to the lungs, also inhibits the ability of the muscles in the airways to expand and contract. Those muscles can in turn weaken, which is why exercise is important for asthmatics to increase their lung capacity. The inflammation also locally damages the lining of the airways, so the body must remodel the lungs. This is where matrix proteinases like ADAM33 are so important; they make sure that the appropriate balance between flexibility and rigidity is achieved.
Airway remodeling is also crucial for premature babies, many of whom develop severe wheezes as a result of the artificial breathing support they must receive. The unusual pressures placed on the developing lungs induce hormone pathways that help the airways recover. But part of the stress response is also to produce the very cytokines that promote inflammation, and which have been independently associated with childhood asthma.
Nevertheless, immune regulation is thought to be by far the most important genetic component to asthma. Many hundreds of studies have asked the question whether a particular allele of one of the dozens of key signaling genes is somehow associated with asthma, eczema, or some biochemical measure of hyperresponsiveness to allergens. The results are a mixed bag. One interleukin in particular, IL-13, has come up as a susceptibility factor in several studies, as has its genomic neighbor IL-4. Both of these are cytokines, little signaling proteins that push the immune system toward a state that is generally affiliated with asthma. The receptors that bind to these signals have also been implicated, as have various proteins that carry the message inside the T-cells. A couple of these are called IRAK proteins, not because they could possibly have something to do with the terror or hypersensitivity of allergic diseases, but because they are Interleukin Receptor Associated Kinases.
A couple of other genes are intriguing as well. One is a bit of an odd-ball member of our old friend the Major Histocompatibility Complex. HLA-G is not one of the picture hangers, but instead is probably involved in mounting the picture on the hangers—that is, the foreign protein fragments on the classical MHC receptors. There are two common variants, but whether they lead to asthma seems to be a function of whether the child’s
mother was asthmatic. If she is, and the child has two Gs at a particular place close to the end of the gene, then he is more likely to be asthmatic as well; if she is not, the same version of the gene may, if anything, be protective.
Mothers’ immune systems have a tendency to see the developing fetus as something foreign, since it has a different genetic constitution after all, including bits from the father. Maybe the HLA-G expression helps her to avoid mounting an immune response against her baby. Probably too the baby ingests amniotic fluid that contains various cytokines that maybe reset the developing fetal immune system. There’s a lot to work out, but it just highlights once more how difficult a job the immune system faces.
One of the high-tech genome-wide association studies has just appeared. The investigators looked at more than 300,000 genetic variants in 1,000 asthmatics and 1,000 nonasthmatics, and once again found suggestive evidence for a dozen or so associations with the disease. Some of these fall in the same regions of the genome as the bits of chromosome we discussed a the beginning of this section. But much the biggest factor is a SNP in the gene ORMDL3. Now that they have looked at more than 5,000 patients, this finding has a less than one in a trillion billion probability of being wrong by chance. You’ll have to read the second edition to find out what ORMDL3 does, because unfortunately no one has much of a clue at this time!
Inflamed Bowels and Crohn’s Disease
Imagine now that instead of attacking a person’s airways, allergic inflammation targeted the other end of the tube that runs down the middle of our bodies, namely the bowels. After a while, thickening of the walls of the intestine and colon would begin to restrict the flow of digested food, leading perhaps to diarrhea and almost certainly to abdominal pain. These digestive organs are full of bacteria, so it is inevitable that some microbes would get into the wounds and provoke ulcers and sores that might manifest as rectal bleeding, with anemia developing as the inflammation became more severe. It is a gruesome thought.
It is also daily life for about 1 in every 200 Americans and Europeans. Inflammatory bowel syndrome comes in two varieties known as Ulcerative Colitis and Crohn’s disease. The differences are too subtle to concern us here; suffice it to say that they are about equally prevalent, and their incidence is rising. Let’s hope it stays below one percent, because although these diseases typically alternate episodes of good health and relapse, there is nothing worse than chronic pain.
For some reason, Crohn’s disease has attracted a lot of attention from the genome-wide association folks, and several studies have now clearly laid out the major genetic components. There are nine of them spread around the genome, each responsible for a few percent of susceptibility. A couple are clearly involved in regulation of the balance of the various arms of the immune system, and another couple are implicated in the ability to digest pathogenic intracellular bacteria such as Listeria. The others all seem to have roles in bowel functions and inflammations, but again the details remain to be worked out.
Like asthma, inflammatory bowel diseases are mostly maladies of the modern hygienic West. They don’t appear on the scene until the 1940s, and then only outside the Tropics and predominately in white people. Plenty of theories are making the rounds—basically you could hypothesize a correlation with just about anything that we did to our world after the Second World War, such as watching television or driving cars—but a couple have a little more substance to them. One is the “cold chain hypothesis” proposed by a French team to explain their observation that Crohn’s disease first became prevalent in North America, then England, and then southern Europe, each a decade or so apart. They blame refrigerators and the industrialization of food storage and production for enabling the spread of pathogenic gut bacteria such as Listeria and Yersinia. These bugs are perfectly capable of growing at low temperatures. There’s a smoking gun in the form of the frequent observation of Yersinia species in the inflamed lesions of patients, though it must be said that it is far from established that these guys are causing the disease in any, let alone most, cases. Maybe there are other similar cold-loving bacteria we don’t even know about yet that also ride the chain of chillers into our intestines where they aggravate at-risk people.
Another idea doesn’t have a catchy name, so we’ll call it the “latrine hypothesis.” About a quarter of the human population is thought to be infected with hookworms, small centimeter-long nematodes that attach themselves to an intestine and gently gorge on blood. They are extraordinarily fecund creatures, each day shedding thousands of eggs that end up in a person’s feces, and subsequently spread around pastures or ditches where people squat in the absence of toilets. When someone treads on infested excrement with bare feet, the hookworms make their way through the skin and over a few days migrate into the lungs where the larvae are coughed up and swallowed, commencing the life cycle all over again. The latrine hypothesis is the proposal that by using latrines on a regular basis, we have broken the life cycle of hookworms, which are thought to be highly protective against inflammatory bowel disease.
Relative to malaria and many other tropical diseases, hookworm infection is benign and in many cases asymptomatic. Ironically, where they occur, the symptoms of hookworm disease are similar to those of the inflammatory bowel diseases they are said to prevent. Hookworms do cause enough anemia and intestinal discomfort to significantly affect quality of life, so the Gates Foundation is supporting vaccination efforts in some parts of the world, such as the Amazon basin. Sewage disposal is even more effective and is the reason why the parasite disappeared from the southern states in the middle of the twentieth century.
Asthmatics and Crohn’s patients alike are starting to consider the possibility that infecting themselves with hookworms might cure their ailments. The Web site www.asthmahookworm.com tells one man’s desperate story of how he went traipsing in human excrement in the Cameroon as a last resort, and how he maintains that his nematode load alleviated his asthma symptoms. I doubt it would work for everyone and don’t advocate his strategy, nor am I sure whether food supplements based on hookworm extracts are likely to do the trick, but we can hope that stories like this help lead to a cure.
Hookworms may exert a protective effect in several ways. One is that they are known to secrete an anticoagulant, which could conceivably counteract inflammation. Another is that they produce their own cytokines that might locally tilt the balance of T-cell responses in the walls of the intestine. Possibly their mere presence in the gut forces the body to mount a soft immune response that also alters the ratio of immune cell types sufficiently to offset the hypersensitive inflammation. For this reason, the cytokine IL4 has emerged from both genetic and immunological studies as a key player in inflammatory bowel syndromes and is currently undergoing clinical trials as a potential cure.
Rheumatoid Arthritis
For tens of millions of Americans, arthritis is a daily burden of chronic pain and discomfort, and the most pressing example of immune disease. We do not know whether or how hygiene and environmental change impact the incidence of arthritis, but once more it provides a compelling example of a complex disease that results from imbalanced activity of genes just trying to do their job.
My mother loves to start each day with a walk up the small mountain behind her home on the outskirts of Canberra. Whenever I return there for a short stay, I make a point of joining her on this ritual as soon as possible. The dry blue skies, familiar whiff of eucalyptus oil, squawks of magpies and kookaburra laughs, often even a glimpse of a pod of eastern gray kangaroos grazing in the underbrush, instantly reconnects me with my country and my childhood. Inevitably, Mum will point to something in the branches, perhaps a sulfur-crested cockatoo or a brightly plumed rosella, and my eyes will search in vain, having followed her outstretched finger bent ninety degrees in the wrong direction. Arthritis has gnarled that finger into a curl.
Why should over half of all elderly people experience this condition because of their genes? I do not want to give the impressio
n that we understand what causes arthritis, but slowly the picture is coming into focus. The high prevalence is a little easier to understand once we recognize that arthritis is actually a suite of diseases that have similar symptoms. It is said to be genetically heterogeneous: Different genes are likely to contribute to each type of arthritis. The rheumatoid form, general inflammation of the joints, is thought really to be matter of friendly fire. The body attacks its own joints, mistaking these as sites of microbial attack. Some of the genes implicated in Crohn’s disease are also susceptibility factors for rheumatoid arthritis.
Osteoarthritis is the other common form. It arises from wear and tear on specific joints as the bones grind over one another. Here the severity of inflammation is more like collateral damage as the immune system deals with bacteria attracted to damaged joints no longer bathed in their protective cartilaginous fluid. My guess is that old baseball catchers have a high rate of arthritis in their knees.
The few percent of people unlucky enough to have severe rheumatoid arthritis are victims of a triple whammy. First, they are predisposed to producing something unfamiliar on their cells as they get older. Then they have been exposed to some sort of an environmental trigger that uncovers that predisposition and causes the something to be produced. Finally, they are susceptible to recognizing it and overreacting. Rheumatoid arthritis is due to an adverse interaction between certain gene flavors, a change in the world around us, and some other flavors of genes.
The molecular players are likely to be different in particular cases, but one example now reasonably well established is as follows. All proteins are assembled from one of 20 common building blocks known as amino acids, one of which is arginine. It turns out that in the majority of rheumatoid arthritic patients, some of their arginines are converted into a similar-looking amino acid called citrulline. These are not to be confused with the foul-smelling lemon essence citronella that burns in candles or incense sticks to keep the mosquitoes at bay on a summer evening. After a time, this conversion of arginines to citrullines makes the patient’s proteins look foreign to their own immune systems. One of the environmental factors that cause this to happen is tobacco smoke. Not content with causing lung cancer, emphysema, and asthma, cigarettes now have been associated with arthritis.
