Why We Get Sick

by Randolph M. Nesse

  It became clear in the 1970s that low iron levels associated with disease could be helpful, not harmful, but even now, Kluger and his associates find that only 11 percent of physicians and 6 percent of pharmacists know that iron supplementation may harm patients who have infections. Although the sample was small, the study illustrates the difficulty of making clinicians aware of some established scientific findings. Even top researchers may neglect to mention this adaptive mechanism. A recent study in The New England Journal of Medicine showed that children with cerebral malaria were more likely to recover if they were treated with a chemical that binds iron, but the article did not describe the body’s natural system for binding iron during infection. The evolved mechanism that regulates iron binding is but one specific illustration of the broader principle that we should be careful to distinguish defenses from other manifestations of infection, slow to conclude that a bodily response is maladaptive, and cautious about overriding defensive responses. In short, we should respect the evolved wisdom of the body.

  STRATEGIES AND COUNTERSTRATEGIES

  Medical researchers are not the only ones who deal with conflicts between organisms. Ecologists and animal-behavior specialists routinely deal with predator-prey relationships, struggles between males for mating opportunities, and many other sorts of conflict. They recognize the evolutionary significance of the phenomena they observe and use such terms as strategy and tactic, winner and loser, and other indications of commitment to the adaptationist program. This approach has been richly rewarding for ecologists and others who are steeped in Darwinism. A similar approach to phenomena such as fever ought to be similarly rewarding in a field of such vital interest to all of us.

  The contest between parasites and their hosts is a war, and every sign and symptom of infection can be understood in relation to the underlying strategies of one or the other belligerent. Some, like fever and iron withholding, benefit the host (defenses); others benefit the pathogen; and a few are incidental effects of the war between them. The strategies are not, of course, products of conscious thought, but they are strategies nonetheless. Bacteria that sneak into the body by pretending to be harmless are rather like Greek soldiers hiding in a wooden horse. When the manifestations of infection are related to conflicting interests, they fit neatly into categories based on their functional importance. Table 3-1 gives an overview of these categories and a guide to the organization of this chapter.

  TABLE 3-1 A CLASSIFICATION OF PHENOMENA ASSOCIATED WITH INFECTIOUS DISEASE

  OBSERVATION EXAMPLES BENEFICIARY

  Hygienic measures taken by host Killing mosquitoes, avoiding sick neighbors, avoiding excrement Host

  Host defenses Fever, iron withholding, sneezing, vomiting, immune response Host

  Repair of damage by host Regeneration of tissues Host

  Compensation for damage by host Chewing on other side to avoid tooth pain Host

  Damage to host tissues by pathogen Tooth decay, harm to liver in hepatitis Neither

  Impairment of host by pathogen Ineffective chewing, decreased detoxification Neither

  Evasion of host defenses by pathogen Molecular mimicry, change in antigens Pathogen

  Attack on host defenses by pathogen Destruction of white blood cells Pathogen

  Uptake and use of nutrients by pathogen Growth and proliferation of trypanosomes Pathogen

  Dispersal of pathogen Transfer of blood parasite to new host by mosquito Pathogen

  Manipulation of host by pathogen Exaggerated sneezing or diarrhea, behavioral changes Pathogen

  How can a host guard against infection? First, it can avoid exposure to pathogens. Second, it can erect barriers to keep them out of the body and act quickly to defend and repair any breaches in the defenses. If pathogens do get beyond the outer ramparts, it can flag any cells that lack proof of identity and expel them from their entry portal. If they have breached this defense line, it can poke holes in them, poison them, starve them, do whatever is necessary to kill them. And if all this does not work, it can wall them off so that they cannot reproduce and spread. If they have done damage, it can repair it. If the damage can’t be repaired immediately, it can compensate for it in some way. Some of this damage and the resulting impairment benefit neither the host nor the pathogen. They are, like the aging bomb craters on the coast of France, just incidental relics of an old battle.

  The pathogens will not, of course, give up readily. Our bodies are, after all, their homes and dinners. We understandably tend to see bacteria and viruses as evils, but how anthropocentric this is! Our defenses attempt to prevent the poor streptococcus from getting even a microgram of our body tissues, but if it cannot find a way around our defenses, it will die. So, for each of our defenses, pathogens have evolved counterdefenses. They find ways to get transmitted to us and ways to breach our walls. Once inside, they hide from our sentries, attack our defenses, use our nutrients to make copies of themselves, and find ways to get those copies out of the body and to new victims, often by turning our own defenses to their own advantage. Before describing the clever stratagems used by pathogens to elude our defenses, we will discuss the defenses in more detail.

  HYGIENE

  The best defense is avoidance of danger; proper hygiene can prevent a pathogen from gaining that first toehold. Instinctively slapping at a mosquito is not just an attempt to spare oneself the minor annoyance of a mosquito bite. It may also prevent a long list of serious insect-borne diseases, of which malaria is the best known. Is the itch of a mosquito bite just part of the insect’s nastiness? It may be merely an accidental result of the chemicals the mosquito uses to ensure that our blood flows freely, but it may also be our adaptation for avoiding future bites. Imagine what would happen to a person who did not mind being bitten by mosquitoes. And imagine how successful a mosquito could be if its biting were not noticeable!

  Our tendencies to avoid contact with people who may be infectious may have the same significance. Likewise, an instinctive disgust motivates us to avoid feces, vomit, and other sources of contagion. Our tendency to defecate away from others may prevent the infection of close associates, and social pressures to conform to such practices may protect us from infection by others. The best defense against infection is avoidance of pathogens, and natural selection has shaped many mechanisms to help us keep our distance.

  THE SKIN

  Our skin is like the wall around an ancient city, a formidable protective barrier. It not only prevents the entry of parasites but also protects against injury by mechanical, thermal, and chemical forces. Unlike induced defenses such as fever, which are aroused only when a particular danger threatens, the skin is constantly present, always on guard. It is tough and much more resistant to puncture and abrasion than the internal tissues it protects. Minor infections here and there are harmless because the skin is constantly being sloughed off the top and renewed from below. An ink stain on the fingers will be gone in a few days, not because the ink has been absorbed or chemically altered but because the stained cells are replaced by others rising from below. Fungal growths or other potential pathogens in surface cells are constantly cast off by this rapid replacement of the epidermis. Sycamores and shagbark hickory trees seem to use the same strategy.

  Not only is the skin a good defensive armor in general, it is also good in particular. Those parts of the body that are most in need of armor, such as the soles of the feet, have thicker and tougher skin right from birth. Any particular patch of skin that is subjected to repeated friction, like that at the top edge of a shoe or the tip of a cellist’s finger, grows the thicker skin we call a callus. This adaptive growth, an induced defense, not only minimizes mechanical injury, it also prevents breaks in the skin that could provide entrances for pathogens.

  Some of our most useful hygienic behaviors help maintain the skin’s barrier. The most obvious are behaviors that keep nasty things off the skin. Scratching and other grooming maneuvers remove external parasites, important sources of discomfort and disease t
ransmission for most people during most of human history and still problems in less fortunate societies. Benjamin Hart, a veterinarian from the University of California at Davis, has shown just how crucial grooming is to preventing illness in animals. An animal that cannot groom is quickly infested with fleas, ticks, lice and mites, and will lose weight and fall ill. The mutual grooming of monkeys is not just a ritual, it is preventive health care.

  PAIN AND MALAISE

  Just as an itch can motivate defensive scratching, pain is an adaptation that can lead to escape and avoidance. The skin, sensibly enough, is highly sensitive to pain. If it is being damaged, something is clearly wrong, and all other activities should be dropped until the damage is stopped and repair can begin. Other kinds of pain can also be helpful. While an abstract realization that chewing is impaired because of an abscessed tooth might possibly lead to more chewing with other, unimpaired teeth, the tormenting pain of a toothache far more effectively prevents the pressure on the tooth that would delay healing and spread bacteria. Continued pain from infection or injury is adaptive because continued use of damaged tissue may compromise the effectiveness of other adaptations, such as tissue reconstruction and antibody attacks on bacteria. Pain motivates us to escape quickly when our bodies are being damaged, and the memory of the pain teaches us to avoid the same situation in the future.

  The simplest way to determine the function of an organ like the thyroid gland is to take it out and then see how the organism malfunctions. The capacity for pain cannot be removed, but very occasionally someone is born without it. Such a pain-free life might seem fortunate, but it is not. People who cannot feel pain don’t experience discomfort from staying in the same position for long periods, and the resulting lack of fidgeting impairs the blood supply to the joints, which then deteriorate by adolescence. People who cannot feel pain are nearly all dead by age thirty.

  Generalized aches and pains, or merely feeling out of sorts (malaise, in medical terminology), are also adaptive. They encourage a general inactivity, not just disuse of damaged parts. That this is adaptive is widely recognized in the belief that it is wise to stay in bed when you are sick. Inactivity also likely favors the effectiveness of immunological defenses, repair of damaged tissues, and other host adaptations. Medication that merely makes a sick person feel less sick will interfere with these benefits. This is fine when patients are well informed about the risks and realize that they are sicker than they feel and should make a special effort to take it easy. Otherwise, a drug-induced feeling of well-being may lead to activity levels that interfere with defensive adaptations or repairs.

  DEFENSES BASED ON EXPULSION

  The body must have openings for breathing, for the intake of nutrients and expulsion of wastes, and for reproduction. Each of these openings offers pathogens an invasion route, and each is endowed with special defense mechanisms. The constant washing of the mouth with saliva kills some pathogens and dislodges others so they can be destroyed by the acid and enzymes in the stomach. The eyes are washed by tears laden with defensive chemicals and the respiratory system by antibody and enzyme-rich secretions that are steadily propelled up to the throat, where they can be swallowed so the invaders can be killed and the protein in the mucus recycled. The ears secrete an antibacterial wax. Projections inside the nose, called turbinates, provide a large surface that warms, moistens, and filters pathogens from the incoming air. Mouth-breathers don’t get the full benefit of this defense and are more subject to infection. The nose and ears have hairs strategically arrayed to keep out insects.

  The defenses at each body opening can be quickly increased if danger threatens. Irritation of the nose by a viral infection provokes the discharge of such copious mucus that one can go through a whole box of tissues in a day. Millions of people use nasal sprays each year to block this useful response, but there are remarkably few studies that have investigated whether the use of such devices delays recovery from a cold. If they do not demonstrably delay recovery, as seems to be the case from the limited data, it would be evidence that a runny nose is not a defense but an example of a pathogen manipulating the host’s physiology in order to spread itself. Sneezing is obviously a defensive adaptation, but not every sneeze need be adaptive for the sneezer. Some sneezing may possibly be an adaptation that viruses use to disperse themselves.

  Irritation deeper in the respiratory tract induces coughing. Coughing is made possible by an elaborate mechanism that involves detecting foreign matter, processing this information in the brain, stimulating a cough center at the base of the brain, and then coordinating muscle contractions in the chest, the diaphragm, and the tubes in the respiratory tract. All along the lining of these tubes tiny hairs called cilia beat in a steady rhythm, sweeping pathogen-trapping mucus upward. In the urinary tract, periodic flushing washes pathogens away along with the cells on the surface of the urethral lining, which are systematically shed like those on the skin. When the bladder or urethra becomes infected, urination understandably becomes more frequent.

  The digestive system has its own special defenses. Bacterial decomposition and fungal growths produce repulsive odors, the repulsiveness being our adaptation to be disinclined to put bad-smelling things into our mouths. If something already in the mouth tastes bad, we spit it out. Taste receptors detect bitter substances that are likely to be poisonous. After we swallow something, there are receptors in the stomach to detect poisons, especially those made by bacteria that multiply in the gastrointestinal tract. When absorbed toxins enter the circulation, they pass by a special group of cells in the brain, the only brain cells directly exposed to the blood. When these cells detect toxins, they stimulate the brain’s chemoreceptor trigger zone to respond first with nausea and then with vomiting. This is why so many drugs are so nauseating, especially the toxic ones used for cancer chemotherapy.

  Circulating toxins almost always originate in the stomach, so it is easy to see how vomiting is useful: it ejects the toxin before more is absorbed. What about nausea? The distress of nausea discourages us from eating more of the noxious substance, and its memory discourages future sampling of whatever food seemed to cause it. Just a single experience of nausea and vomiting after eating a novel food will cause rats to avoid it for months; people may avoid it for years. This remarkably strong onetime learning was named the “sauce béarnaise syndrome” by Martin Seligman, a psychologist who recognized its significance after contemplating the untimely loss of his gourmet dinner. Why is the body capable of such a strong association after a single exposure to a food that produces illness? Imagine, for a moment, what would happen to the person who ate poisonous foods repeatedly.

  The other end of the intestinal tract has its own defense, diarrhea. People understandably want to stop diarrhea, but if relief comes from merely blocking the defense, there is likely to be some penalty. Indeed, H. L. DuPont and Richard Hornick, infectious disease experts at the University of Texas, found just this. They infected twenty-five volunteers with Shigella, a bacterium that induces severe diarrhea. Those who were treated with drugs to stop the diarrhea stayed feverish and toxic twice as long as those who did not. Five out of six who received the antidiarrheal drug Lomotil continued to have Shigella in their stools, compared to two out of six who did not receive the drug. The researchers concluded, “Lomotil may be contraindicated in shigellosis. Diarrhea may represent a defense mechanism.” Consumers will no doubt want to know when they should and should not take such medications for more commonplace diarrhea, but the needed research has not been done. There are dozens of studies of side effects, of safety, and of the effectiveness of medications that block diarrhea, but few consider the consequences of the main effect of blocking a normal defense.

  Our reproductive machinery requires yet another opening, which in males is the same as that of the urinary tract, whose defenses thereby do double duty. Women have a separate opening that poses a special problem for defense against infection. While the female reproductive tract uses many defenses, such as c
ervical mucus and its antibacterial properties, one largely unappreciated defense is the normal outward movement of secretions that makes it difficult for bacteria and viruses to gain access. These secretions move steadily from the abdominal cavity through the fallopian tubes, uterus, cervix, and vagina to the outside. There is one noteworthy exception to this constant downstream movement. Sperm cells swim upstream, from the vagina through the uterus into the fallopian tubes and the pelvic cavity. Unusually small for human cells, sperm are still large compared to bacteria. Potential pathogens can stick to sperm cells and be transported from the outside to deep within a woman’s reproductive system.

  Only recently has the threat of sperm-borne pathogens been recognized. Biologist Margie Profet notes that menstruation has substantial costs and argues that it must therefore give some compensating benefit. After a consideration of the evidence, she concluded that many aspects of menstruation seem designed as an effective defense against uterine infection. The same anti-infection benefits that come from sloughing off skin cells are achieved by the periodic extrusion of the lining of the uterus. This is supported by evidence that menstrual blood differs from circulating blood in ways that make it more effective in destroying pathogens while minimizing losses of nutrients. Studies of menstruation in other mammals suggest that each species menstruates to just the extent appropriate for its vulnerability to sperm-borne pathogens. The threat is small for species that restrict their sexual behavior to widely separated fertile periods, but women’s continuous sexual attractiveness and receptivity are largely unrelated to the ovulatory cycle. This extraordinary amount of human sexual activity may have its benefits, as we will discuss in Chapter 13, but it substantially increases the risk of infection. This risk may be responsible for the unusually profuse human menstrual discharge, as compared to other mammals’.