Why We Get Sick

by Randolph M. Nesse

  An alarming increase in the occurrence of melanoma, a potentially fatal skin cancer, is causing a justified fear of excessive exposure to the sun. The rates in Scotland have doubled in the past decade, and the rates among fair-skinned people are increasing at a rate of 7 percent a year in many countries. Explanations for the increase range from the new cultural desire to be tan to the thinning of the ozone shield, which has always blocked much ultraviolet light. While both of these factors need to be considered, an evolutionary view suggests other explanations too. We do spend more time at beaches, but we spend far less walking in the sun without clothes on. The loss of ultraviolet blocking resulting from ozone depletion is more than counterbalanced in most areas by the local air pollution. What is new is not sun exposure or ozone inadequacy but our pattern of sun exposure. People now spend most of their time indoors and then go outside on weekends for intense bouts of unaccustomed exposure. People who are outdoors for hours every day adapt to their amount of usual exposure and are unlikely to get sunburnt. The risk of melanoma is related more closely to the number of sunburns than to the total amount of time spent in the sun.

  Another novel environmental factor is the use of chemically complex sun lotions. Blocking ultraviolet radiation does curtail the development of cancerous lesions. A recent controlled study of 588 Australians found that those who used an active sunscreen developed significantly fewer precancerous skin lesions than those who used a cream that did not block much ultraviolet light. But might the chemicals in sunscreens also cause problems? They don’t just sit on the surface of the skin but are absorbed into it. What effects do they have on skin cells, and how might they be transformed after binding to tissue proteins and being bombarded by strong light? The answers are very much in doubt. How ironic it would be if we were to discover that skin cancer can be caused, directly or indirectly, by suntan lotions! Attention should also be given to the products used to inhibit the inflammatory process of sunburn. Such inhibition might prevent cancer by preventing unnecessary damage from autoimmune reactions, but it might also protect damaged and potentially cancerous cells from being naturally destroyed by the immune system.

  We emphasize that these are not facts but mere speculations that arise from our lack of understanding. Why do we understand so little about sunburn despite the abundance of available information? Understanding that provides a reliable basis for protection and therapy will be reached when researchers well versed in evolutionary reasoning and with a detailed knowledge of the cellular and molecular events of sunburn put together an explanation that: (1) distinguishes UV impairment of skin function from its adaptive responses to UV stress; (2) distinguishes UV impairment of the immune function from the adaptive immune response; (3) distinguishes impairment of Langerhans cell function from adaptive responses; (4) delineates the special components of the repair processes and their coordination; and (5) shows the positive and negative effects of protective lotions applied before exposure and anti-inflammatory medications used afterward.

  Sun damage also appears to contribute to cataracts, a clouding of the lens in the eye. While most sunglasses now block ultraviolet light, older models often did not. Instead they reduced the total amount of visible light, so that the pupil actually opened more widely and admitted more ultraviolet light. Worse yet, many of the cheap sunglasses that children are likely to wear still transmit large proportions of the ultraviolet. We wonder whether some of today’s cataract patients might owe their misfortune to sunglasses they wore decades ago.

  REGENERATION OF BODY PARTS

  Children often ask the most intelligent questions. “Why,” asks an inquisitive child, “can’t Uncle Bob grow a new leg like a starfish does?” Why not indeed? If lizards regrow lost tails, starfish lost arms, and fish lost fins, why can we not even regenerate a lost finger? It is remarkable that this question seldom bothers adults, even biologists. The answer, in general evolutionary terms, is that natural selection will not maintain capacities that are unlikely to be useful or that have costs that would exceed the expected benefits. Thus, as noted in Chapter 3, serious damage to the brain or heart was uniformly fatal before the era of modern medicine, and the ability to regenerate these tissues could not be selected for. An individual who lost an arm in a Stone Age accident could bleed to death in a few minutes. If the bleeding were somehow controlled, the victim would likely soon die of tetanus, gangrene, or other infection. Any process that might have allowed our remote ancestors’ arms to regenerate has gradually been lost by the accumulation of mutations that have not been selected against.

  But what about the loss of a finger? This would not be as likely to cause death as the loss of a whole arm, and such injuries often do heal under Stone Age conditions. Why not regenerate the finger instead of merely healing the wound? The explanation given in the previous paragraph will not suffice here. We suggest instead two other factors. The first is merely that this regenerative ability would not be used very often and would not produce a major benefit. Most people do not lose fingers, and if they do, the long-term impairment need not be serious. A nine-fingered Neanderthal might live to the ripe old age of fifty. Another reason, which we have already repeatedly emphasized, is that every adaptation has costs. The capacity to regenerate damaged tissue demands not only the cost of maintaining the machinery to make this possible but also the cost of a decreased ability to control harmful growths. A mechanism that allows cell replication increases the risk of cancer. It is dangerous to let mature, specialized tissues have more than the minimum needed capability to repair likely injuries, as we will discuss in the chapter on cancer.

  A different kind of explanation is often offered for our inability to regenerate a missing finger. Regeneration would require growth hormones, control of cell movement, and many other processes, and they are simply not there. This is another way of saying that, after an early stage of fetal development, the machinery needed for producing a finger is missing. This is the sort of proximate explanation, based on the details of the mechanism, that most medical researchers would think of first. But we also need an evolutionary explanation of why the needed machinery is missing, whatever that machinery might be. Such an evolutionary explanation is more likely to satisfy a child’s curiosity, and it can lead researchers to fruitful ideas on what sort of repair machinery we might expect to be activated by the loss of a finger. We suggest that the machinery will conform to an optimal tradeoff between the advantages of rapid and reliable repair, the costs of the needed machinery, and the dangers of cancer.

  6

  TOXINS: NEW, OLD, AND EVERYWHERE

  “Nat,” says Don Birnham (Ray Milland) to his bartender in The Lost Weekend, “You don’t approve of drinking. Shrinks my liver, doesn’t it? It pickles my kidneys. Yes, but what does it do to my mind?” We will consider the effects on his mind in later chapters. Here we will merely mention some effects prior to those on his liver and kidneys.

  Don’s rye whisky rewards him with a gentle burning sensation as it passes through his esophagus and on to his stomach. His nerves are signaling the deaths of millions of cells as alcohol diffuses rapidly through the usually protective barrier of mucus and enters those cells. If a cell gets more than a critical concentration of alcohol, it dies. Dead cells, or even those with damaged membranes, release wound hormones and growth factors, which diffuse to other cells held in reserve for just such an emergency. These reserve cells, deep in the protected crypts of the stomach lining, react to the chemical messages by migrating to the site of injury and dividing to produce new cells of the kind needed there. The most exposed layer of stomach cells can be replaced in mere minutes—but does Don allow them enough time before quaffing again?

  NATURAL AND UNNATURAL TOXINS

  High-proof alcohol is only one of the many novel hazards to which we are exposed. Agricultural pests are controlled mainly by insecticides that did not exist before 1940. Silos are perfused with poisonous vapors to protect grain from insects and rodents. Demonstrably toxic chemicals
such as nitrates are used to extend the shelf life of our foods. Many workers inhale toxic dust or fumes, and suburbanites spray insecticides such as lindane into their trees, often with little regard to the possible effects on themselves or their neighbors. There are heavy metals in our water, pollutants in our air, and radon gas rising from our basements. Obviously our modern age is especially hazardous, with respect to poisons in the food we eat and the air we breathe. Right?

  Wrong. While we are now exposed to many toxins that did not exist in even the recent past, our exposure to many natural toxins has greatly decreased since the Stone Age and early agricultural times. Recall from the chapters on infectious disease that the contest between consumer and consumed can generate an evolutionary arms race. Plants can’t protect themselves by running away, so they use chemical warfare instead. People have always known that some plants are toxic. Gardening books routinely list plants known to have caused illness or death from being eaten. These lists merely deal with the worst offenders. Most plants contain toxins that would be harmful if eaten in more than a minimal amount. Scientists have only recently realized that the toxic substances are not by-products that just happen to be toxic to certain potential consumers; they are the plants’ essential defenses against animals that want to eat them (herbivores), and they play a key role in the ecology of natural communities. People who live in the eastern United States needn’t look far for an example. Most lawns there are of tall fescue, a grass species popular because it grows fast and resists pests. The fantasy of getting rid of our lawn mowers and letting horses graze our lawns once a week is appealing, but the horses would soon get sick. Most tall fescue is infected at its base with a fungus that makes potent toxins. The grass protects itself by transporting these toxins to the tips of the blades of grass, the perfect location for discouraging herbivores. Tall fescue and its fungus help each other.

  Only very recently have a few pioneers, such as Timothy Johns and Bruce Ames and his collaborators, made us aware of the enormous medical importance of the plant-herbivore arms race. We can heartily recommend Johns’s book With Bitter Herbs Thou Shalt Eat It for an introduction to the role of plant toxins in human history.

  Here we are again dealing with an arms race, this time between animals such as ourselves, who eat plants, and the plants, which need to protect themselves from being eaten. When Stone Age inhabitants of central Europe died of starvation late one winter instead of happily filling up on oak buds and acorns, they were losers in the contest with oak trees. Oak buds and acorns are loaded with nutrients, but, unfortunately for potential consumers, they are also loaded with tannins, alkaloids, and other defensive toxins. Early Europeans who filled up on unprocessed oak tissues died even sooner than their starving companions did.

  Animals that eat other animals may have to deal with venoms or other harmful materials manufactured by their prey, and they will certainly have to deal with at least traces of the plant toxins eaten by the prey. The monarch butterfly caterpillar, mentioned earlier, feeds on milkweed not only because it has machinery that makes it invulnerable to the milkweed’s deadly cardiac glycosides but also because it becomes poisonous itself by consuming the plant and is therefore avoided by potential predators. Many insects and arthropods protect themselves with venoms and poisons. Many amphibians are poisonous, especially the bright-colored frogs that Amazonian peoples use to poison their arrowheads. The vivid colors and patterns of such poisonous animals protect them from predators, who have learned from bitter experience that such prey are not pleasant food items. If you are starving in a rain forest, eat the camouflaged frog that is hiding in the vegetation, not the bright one sitting resplendent on a nearby branch.

  How do plant toxins work? They do whatever will keep herbivores from eating the plants. Why are there so many different toxins? Herbivores would quickly find a way around any one defense, so the arms race creates many different ones. The list of different toxins and their diverse actions is impressive. Some plants make precursors of cyanide, which is released either by enzymes in the plant or by the intestinal bacteria of the consumer. The bitter almond is noteworthy in this regard, but apple and apricot seeds use the same strategy, as do cassava roots, which are used for food in many cultures.

  All adaptations, however, have costs, and plants’ defensive chemicals have theirs. Toxin manufacture requires materials and energy, and the toxins may be dangerous to the plant that produces them. In general, a plant can have high toxin levels or rapid growth, but not both. To put it from the herbivore’s point of view, rapidly growing plant tissues are usually better food than stable or slowly growing structures. This is why leaves are more vulnerable than bark and why the first leaves of spring are especially vulnerable to caterpillars and other pests.

  Seeds are often especially poisonous, because their destruction would thwart the plant’s reproductive strategy. Fruits, however, are bright, aromatic packets of sugars and other nutrients specifically designed to be attractive food for animals that can disperse the seeds contained in them. The seeds within the fruit are designed either to be discarded intact (like peach pits) or to pass safely through an intestinal tract (like raspberry seeds) to be deposited at some distant place surrounded by natural fertilizer. If the fruit is eaten before the seeds are ready, the whole investment is wasted, so many plants make potent poisons to discourage consumption of immature fruits, thus the proverbial stomachache caused by green apples. Nectar is likewise designed to be eaten, but only by whatever pollinators are best for the plant that makes it. Nectar is an elaborate cocktail of sugar and dilute poisons. The recipe has evolved as an optimal trade-off between the need to repel the wrong visitors and not discourage the right ones.

  Nuts represent a still different strategy. Their hard shells protect them from many animals, and some, like acorns, are also protected by high levels of tannin and other toxins. Though many acorns are eaten, some are trampled into the ground, while others are buried by squirrels and thus have a chance to sprout into new trees. It takes such elaborate processing to turn acorns into human food that we wonder if the tannin may be too much even for squirrels. Perhaps it leaches out when acorns are buried in moist soil. If so, the squirrels are processing as well as hiding their food, a neat ploy in their arms race with the oak. If you find yourself starving in an unknown wilderness, seek your nourishment in soft sweet fruits, the nuts with the hardest shells, and perhaps some inaccessible tubers. Avoid seemingly unprotected fleshy plant materials like leaves; they are much more likely to be poisonous, as they must be to protect them from your own or any other hungry mouth.

  Plants’ escalations of the arms race are numerous and varied. Some plants make little defensive toxin until they are mechanically damaged, after which toxin rapidly accumulates in or near the injured part. Damage to a tomato or potato leaf induces production of toxins (proteinase inhibitors) not only at the site of the wound but throughout the plant. A plant has no nervous system, but it does have electrical signaling and a hormone system that can keep all its parts informed about what takes place in a small region. Some aspen trees have even more impressive communication. When a leaf is damaged, a volatile compound (methyl jasmonate) evaporating from the wound can turn on the proteinase response in nearby leaves, even those on other trees. The usual result of such defenses is that insects are discouraged after feeding even briefly. Some particularly adept insects, however, begin their meal by cutting the main supply vein to a leaf so the plant cannot deliver more toxins. And so the arms race goes on.

  DEFENSES AGAINST NATURAL TOXINS

  The best defenses are, of course, the sorts of avoidance and expulsion already discussed in relation to infectious diseases. We avoid eating moldy bread or rotten meat, which smell and taste bad, because we react with an adaptive disgust to the toxins produced by fungi and bacteria. We rapidly expel toxic substances by spitting or vomiting or diarrhea. We quickly learn to avoid whatever gives us nausea or diarrhea.

  Many swallowed toxins can be denatured by
stomach acid and digestive enzymes. The stomach lining is covered with a mucous layer that protects it from ingested toxins and stomach acid. If some cells become contaminated, the effect is temporary since stomach and intestinal cells, like those of the skin, are shed regularly. If toxins are absorbed by the stomach or intestine, they are taken by the portal vein directly to the liver, our most important detoxification organ. There, enzymes alter some toxic molecules to render them harmless and bind others to molecules excreted in the bile back into the intestine. Toxin molecules in sufficiently low concentration will be quickly taken up by receptors on cells in the liver and rapidly processed by the liver’s detoxification enzymes.

  For instance, our protection against cyanide depends on an enzyme called rhodanase, which adds a sulfur atom to cyanide to form a chemical called thiocyanate. Although thiocyanate is far less toxic than cyanide, it still prevents the normal uptake of iodine into thyroid tissue and thus can cause the overworked thyroid gland to enlarge—a condition called goiter. Plants from the genus Brassica (including broccoli, Brussels sprouts, cauliflower, and cabbage) get their strong taste from allylisothiocyanate. The ability to taste a related compound, phenylthiocarbamate (PTC) varies greatly, as is well known by generations of students who have tasted a bit of PTC-impregnated filter paper as part of an experiment to demonstrate genetic variation. While some people can’t taste PTC, those with a different gene experience it as bitter. They may have an advantage in avoiding natural compounds that cause goiter. About 70 percent of individuals in most populations can taste PTC, but in the Andes, where such compounds are especially likely in the diet, 93 percent of the native people can taste it.