It Takes a Genome: How a Clash Between Our Genes and Modern Life is Making Us Sick

by Greg Gibson

  For millions of years primates had a relatively constant range of pressures and evolved a system of hormones based around insulin, leptin, and some others that worked pretty efficiently. Then we decided as a species to start migrating around the world, to have odd monthly menstrual cycles, and to live longer than we were ever meant to. At various times we’ve switched from being herbivores to carnivores to omnivores, from hunter-gatherers to pastoralists, and most recently to cornivores. Our metabolic systems are stressed and confused.

  Disequilibrium. Imbalance. Desynchronization. Instability. Mismatch. Call it what you will, but the fundamental problem is that our modern lifestyle is out of step with the genetic legacy of millions of years. Our omnivorous diet exposes us to a much wider range of toxins and pathogens than most species see, putting pressure on the exquisite network of cytokines and other signaling molecules that regulate fat and sugar metabolism.

  Our wanderings have exposed us to such a wide range of climates and food sources that the metabolic system is forced to adapt locally. All these pressures and others are nudging the metabolic genetic network away from a balance forged over the course of mammalian evolution. More than a third of all people living in developed countries are now at risk for a metabolic syndrome of ill health that includes diabetes and heart disease. It will take tens, if not hundreds, of thousands of generations to find a new equilibrium to cope with the impact of a few thousand generations of profound perturbation.

  Disequilibrium also exists between the energy dense Western diet and our genetic constitution, however, it has been shaped by human evolution. When you push any well-buffered system to the limits, it breaks down. We push the biochemistry and physiology of glucose homeostasis to the limits every day, and it is inevitable that some genetic combinations are less able to cope than others.

  What to do about it? Western practice is to treat the symptoms. More drugs, please! Eventually, perhaps too society will call for eugenic approaches that will rid the gene pool of this scourge. Surely we will recognize instead that it is much easier and more human to change attitudes and shift lifestyles. Change what we eat and how we eat, and change our parenting practices that permit or even encourage young children to adopt the very habits that threaten their future happiness.

  4. Unhealthy hygiene

  athletic asthmatics Asthma is a modern disease that is the largest source of morbidity for children in the developed world, but happily can be overcome with appropriate attention.

  inflammation and respiration Respiratory illnesses are an example of inflammatory diseases that result in part from inappropriate function of the immune system.

  the hygiene hypothesis Part of the reason for the rising prevalence of asthma may be the great improvements in cleanliness and hygiene that characterize modern life.

  asthma epidemiology However, hygiene is certainly not the whole story: Geography, socioeconomic status, and genetics all play their parts.

  genetics of asthma Risk factors include immune regulators, genes involved in muscle function in the airways, and numerous others whose functions remain to be worked out.

  inflamed bowels and crohn’s disease Inflammatory bowel syndromes have similar genetic attributes and also seem to be exacerbated in the modern environment.

  rheumatoid arthritis Arthritis is yet another inflammatory disease, of the elderly rather than the young.

  imbalance of the immune system These diseases all reflect the imbalance between the recently evolved human genome and the constantly changing contemporary environment.

  Athletic Asthmatics

  A small boy passes his night crunched up in fits on his bed, chest to knees and forehead to pillow, just trying to suck enough air into reluctant lungs to feel comfortable enough to sleep. This incidence of mild asthma was brought on by who knows what, perhaps the tobacco smoke seeping out of his father’s study, maybe the cat fur balled up under the old couch in the living room, or even something as innocuous as a mold hiding in the black bean sauce from last night’s Chinese take-out.

  Not that asthma is a new ailment: A long list of prominent figures in the Arts and Sciences testifies that it is an obstacle readily overcome by those of firm purpose. Politicians and revolutionaries of various ilk have suffered. On the one hand, the Central American activist Ché Guevara and Peter the Great of Russia; on the other an extraordinary group of five of the last 16 United States Presidents, including Teddy Roosevelt and John F. Kennedy.

  Dozens of Olympic champions and professional athletes have brushed aside severe asthma en route to their ascendancy. Amy Van Dyken, winner of four gold medals in the pool at the 1996 Atlanta Summer Olympics, may be the most impressive example. Apparently her childhood affliction, induced variously by infection, allergies, and exercise, was so severe that on bad days she could barely laugh, let alone climb a flight of stairs. At the age of 11, she could not yet swim the length of a competition pool, but a dozen years later she was the fastest butterfly and medley swimmer in the world. It is hard to imagine two events more demanding on the lungs than these—except perhaps for the 400-meter freestyle. The Thorpedo, Ian Thorpe, one of the greatest middle-distance swimmers of all time, also took up the sport in an effort to increase his lung capacity to overcome childhood respiratory problems. He even had to overcome an allergy to the chlorine in pools, all without the help of steroidal antiinflammatories, which, of course, are on the list of banned substances for elite athletes.

  On the track, Jackie Joyner-Kersee presents a different case study. In 1993, at the height of her career as one of the most dominating heptathletes of all time, she had an attack so acute that it almost took her life. She says it was like someone shoving a pillow over your face, completely blocking off the supply of oxygen. Jackie was not actually diagnosed with the disease until she was a freshman in college, having denied that there was a problem and hidden it from her coaches until then. After several trips to emergency care, she finally accepted the need for medical treatment and started down a path not just of recovery but also of athletic improvement. That she mastered the grueling two-day challenge of hurdles, high jump, shot-put, sprint, long jump, javelin, and middle-distance running should serve as an inspiration to anyone who feels grounded by the disease.

  Jerome “the Bus” Bettis, lovable burly running back for the Pittsburgh Steelers, has a similar story of a turning point in his approach to the disease following a near-fatal attack during a televised game in 1997. His problem was diagnosed in high school and dealt with well enough that he thought he had outgrown it, so he relaxed his attention to the medical program. He fell into the bad habit of taking his inhaler only when he thought it was necessary, but says that this complacency ultimately led to his brush with death. Since then he has faced the disease with the same tenacity and force with which he hit the holes opened up by his offensive line over a decade of bruising football.

  Childhood asthma is much more common than adult-onset, and most kids grow out of it to some degree, but it is a chronic disease possessed by 17 million Americans. This number is projected to double in the next 20 years, as it did over the preceding two decades. Five thousand deaths, 500,000 hospitalizations, and almost two million emergency room visits annually tell the tale of a major public health problem. Most attacks are said to be avoidable if only people pay attention to warning signs and stick to their medications. These include corticosteroids to control chronic inflammation of the airways, and bronchodilators to be taken prior to exercise or exposure to other triggers. Van Dyken, Joyner-Kersee, and Bettis are now three of the most prominent public figures of the Asthma All-Stars program dedicated to spreading the word about how the disease can be controlled.

  Inflammation and Respiration

  Inflammation is the body’s natural response to a crime against it. Whether the agent is an insect bite or the sting of poison ivy, the aggressive swelling around a nasty cut, or an allergic response to house dust mites, there are commonalities in the way the immune system responds. When a
crime occurs, our first response is to cordon off the area. Then we send in various experts to deal with the problem: police, emergency medical technicians, forensic detectives, clean-up crews. The crime scene becomes a hive of activity, set apart from regular day-to-day life.

  So too with inflammation. The word comes from the Latin to “set on fire.” It refers to an acute reaction characterized by redness, swelling, heat, and pain. These are things that follow from the opening up of the blood vessels at the scene of the crime where red and white blood cells are given access to the injury. If the skin has been breached, they initiate a cascade that will close the wound with a blood clot. If the wound has an allergic trigger, it will cause a big red rash, which may become an itchy skin condition known as atopy, eczema, or atopic dermatitis if you want to be really technical. Milder irritation of the airways gives rise to asthma.

  One of the fascinating things about atopy is that it has increased dramatically in prevalence over the past few decades, both in dogs and in human children. The first recorded cases of canine atopy appear in the scientific literature just 50 years ago, but it is now estimated that upwards of ten percent of all dogs have irritable skin conditions. Atopy is closely associated with asthma in humans, but asthma is almost unheard of in dogs, while quite common in horses. Genetics predisposes in strange ways.

  Hay fever is perhaps the most common inflammatory disease, a classical case of overreaction to a perceived threat. You can think of hay fever as asthma of the nose. North Carolina is covered with beautiful shortleaf and loblolly pines that grace its golf courses and lately frame its subdivisions. Every spring they blanket everything—cars, roofs and unsuspecting eyelids—in a bright yellow pollen, that if millimeters thick on the ground is predictably obnoxious to sinuses.

  Confronted with unwanted pollen, circulating molecules known ignominiously as IgE strike up the alarm by signaling mast cells to secrete histamines at the site of intrusion. Both IgE and histamines are generally good guys, the former doing its best to serve as advance warning scouts for infection, and the latter helping out with other vital functions such as sleeping and having orgasms. But in pollen season they can be a nasty combination for those with a particularly sensitive disposition.

  Asthma itself is a chronic condition where a person is at constant risk of having an attack triggered by the slightest perturbation, whether contracting a virus, reacting to a change of temperature or pollutants in the air, or stressing the lungs while exercising. Attacks are generally indicated by tightening of the chest and shortness of breath. It is like trying to breathe with someone sitting on your chest. Then as the inflammatory process builds up, mucus lines your bronchi and characteristic wheezing appears, sometimes accompanied by a persistent cough. Untreated, attacks can so severely cut off the oxygen supply that a patient’s extremities will turn blue and cold, before they pass out, and possibly die from asphyxiation.

  One big difference between asthma and hay fever is that the response to allergens is mediated by the more sophisticated T-cells, rather than just by IgE. Whatever is in the air that irritates an asthmatic is actually digested by professional cells whose role it is to present a chopped up fragment of the invader to the T-cells that mount a full-fledged inflammatory response. This is similar to what happens in type 1 diabetes, except that it is a foreign substance rather than insulin that is being presented to the immune system. And the immune system attacks the infected cells in the upper lungs or nose (rather than the pancreatic cells that make the insulin). In general it is a good strategy, but some people are more prone to mounting an unnecessarily severe response. Understanding why is the key to appreciating why there is genetic variation affecting asthma.

  Short-term relief during an attack is generally provided by bronchodilators delivered through an inhaler. These drugs stimulate the airway muscles to relax. Albuterol is the best known. The same drug is also taken intravenously to prevent premature childbirth since it relaxes the uterine muscles just as effectively. Ten or so similar drugs are on the market, prescribed according to strength, length of activity, and whether they cause tremors as they act on other muscles in the patient.

  Long-term relief comes in the form of corticosteroids, which act to dampen the likelihood of an inflammatory reaction in the first place. As anyone who follows sports knows, steroids are a mixed blessing. They may have immediate benefits, but taken over a long period of time they are a risky business (quite apart from the potentially career-ending consequences of being caught). They are known to upset glucose metabolism and increase weight gain, so predispose to diabetes. They also promote osteoporosis by weakening bone development, and through their impact on muscle mass can so change the heart that they can cause cardiovascular failure later in life. It just doesn’t seem such a good idea to take something that grows facial hair on women and gives men biceps rounder than their thighs, but in a way, this is what chronic asthmatics are forced to do.

  The Hygiene Hypothesis

  Of course, it would be better if we could prevent kids from being exposed to the allergens and toxins that are setting off asthma in the first place. Imagine a world without cigarette smoke and diesel fumes for breakfast, and we’re probably halfway there. Yet according to an increasing body of thought, that same imagining of a world less prone to inflammatory disease would also encourage us to expose our toddlers to all sorts of viruses and bacteria, and to deliberately infect sensitive adults with intestinal hookworms.

  The essence of this idea is embodied in “the hygiene hypothesis.” First proposed by a British physician, David Strachan, in 1989, the hygiene hypothesis suggests that a large part of the increase in allergic inflammatory diseases in the twentieth century is attributable to the unusually sanitary conditions in which we now live. The immune system requires a delicate balance of efforts to fight diverse viruses, bacteria, and parasites. This must be primed during childhood, but since infants are no longer exposed to a traditional barrage of pathogens, they don’t get the balance right. Hypersensitivity to unusual allergens follows, like weeds after a cleansing rainfall.

  The idea is simple and compelling. Trouble is, there is precious little evidence that it is correct, at least as a general explanation for the epidemic nature of asthma. Like the thrifty genes hypothesis in Chapter 3, “Not so Thrifty Diabetes Genes,” a great concept seems to succumb to the belligerent absence of evidence. Except that in this case, I’m willing to wager that the idea is right, and we just haven’t worked out how to prove it: There is equally little evidence that the hygiene hypothesis is wrong—particularly since it is proving to be a remarkably adaptable hypothesis. The initial observation led Dr. Strachan to propose that the incidence of hay fever and eczema decline as families get larger. Furthermore, younger kids are less likely to suffer from these diseases, suggesting that they have been protected by exposure to all the ugly microbes that their older siblings brought into the house. Fifteen years later, Strachan used expansive hospital records to test his prediction that the decline in family size in England correlates with the ongoing increase in asthma prevalence. The results were equivocal, so it doesn’t look like this simple form of the hypothesis is all there is to it.

  Others have tested related predictions, also finding general consistency with the idea that improved hygiene increases the likelihood of asthma. Kids who attend day care and are exposed to a scary menagerie of bugs seem to be less predisposed to allergic illnesses. So too with kids who grow up on farms, rolling in the hay and sleeping with who knows what strange microbial bedfellows. Of course, they also grow up less likely than city kids to appreciate the difference between a cappuccino and a macchiato, a chardonnay and a pinot grigio, or ecstasy and heroin. Life is full of trade-offs that affect our health.

  I have not seen it commented on anywhere, but the parallels between urbanization and asthma prevalence, and affluence and polio incidence are striking. Poliomyelitis is a viral disease that terrorized the United States and Europe for a couple of decades in the midd
le of the last century but has now been eradicated from all but the Indian subcontinent and tropical West Africa.

  Its most famous victim was Franklin Delano Roosevelt, and its most enduring consequence has been the birth of biomedical philanthropism. Together FDR and his law partner, Basil O’Connor, marshaled heart-string appeals to the general populace to raise enough money to treat polio victims across rural America. Their March of Dimes Research Foundation was almost singlehandedly responsible for supporting development of Jonas Salk’s vaccine that conquered the disease in America. The Foundation continues to support research into birth defects—in fact, they gave me my first research grant a dozen years ago. Today’s Howard Hughes, Wellcome Trust, and Gates Foundations, among others, trace a direct line of descent to the March of Dimes proposition that philanthropy has a crucial role to play in curing common diseases.

  The odd thing about polio, though, is that it was well known to preferentially afflict affluent white folk. It struck without warning, sometimes restricting itself to one highly athletic and active adult, at other times afflicting a whole family of children at once. We know now that the vast majority of infections are transmitted from feces to mouth, namely because of bad hand-washing practices, which is as good a reason as any to heed the signs in restaurant restrooms.