A FUNCTIONAL APPROACH TO DISEASE
We end this chapter by making three remarks about Table 3-1 (this page), which classifies the signs and symptoms of infectious disease according to their functions. First, a functional classification of the signs and symptoms of disease is important and useful. In order to choose appropriate treatment, we need to know if the cough, or other symptom, benefits the patient or the pathogen. We also need to know if the pathogen is manipulating the host or attacking its defenses. Instead of just relieving symptoms and trying, perhaps ineffectively, to kill the pathogen, we can analyze its strategies, try to oppose each of them, and try to assist the host in its efforts to overcome the pathogen and repair the damage. The second point is that the classification is really rather simple and obvious.
Now for the third point: When and by whom do you think the ideas in this chapter were first proposed? Was it by some nineteenth-century medical researcher building on the ideas of Pasteur and Darwin as well as the rapidly expanding body of knowledge of parasite life histories? No. The classification scheme used in our table and throughout this chapter was first proposed at the University of Michigan in 1980 by Paul Ewald, an ornithologist and evolutionary biologist now at Amherst College. And when did the ideas in this chapter first become standard elements in the thinking of physicians and medical researchers? The answer to this question is a simple and discouraging not yet. We do not mean that physicians never intuitively think in the categories formalized by Ewald. We merely mean that they have not been explicitly taught to use them and that deficiencies of training make it easy to neglect these essential ideas in thinking about infectious disease. There is hope, which is especially evident in the proceedings from several recent conferences that have emphasized the benefits of interchange between evolutionists and infectious disease experts. But it will still be years before this sort of material becomes part of the regular medical curriculum.
Why has the medical profession not taken advantage of the help available from evolutionary biology, a well-developed branch of science with great potential for providing medical insights? One reason is surely the pervasive neglect of this branch of science at all educational levels. Religious and other sorts of opposition have minimized the impact in general education of Darwin’s contributions to our understanding of ourselves and the world we live in. There has also been a peculiar neglect of evolution in the training of physicians and medical researchers, a matter discussed further in Chapter 15.
Still another reason is that many of the evolutionary ideas of greatest bearing on medicine have only been formulated in recent years. These ideas are often simple and not very different from common sense—once they are pointed out. Yet their recognition and the appreciation of their importance have come only in the past few years, far behind the development and application of many really complex and subtle branches of physical science and molecular biology. Exactly why the application of evolutionary biology to medicine and other aspects of human life has advanced so slowly after its magnificent inception in 1859 is a question that ought to be getting major attention from historians of science.
4
AN ARMS RACE WITHOUT END
Every time a nation or a tribe designs a new weapon, a competing nation or tribe will soon devise a counterweapon. Thus spears and swords gave rise to shields and body armor, and radar defenses to the Stealth Bomber. Likewise, the evolutionary origin of a predator’s improved hunting technique can be countered by the prey’s improved armor, evasive tactics, or other defensive adaptation, which is then met by countermeasures from its predators. If foxes start running faster, rabbits are selected to run even faster so that foxes must run faster still. If foxes’ eyesight improves, this selects for rabbits that blend better with the background, which may select for foxes that can locate rabbits by smell, which in turn may select for rabbits that tend to move downwind from foxes. Thus predator and prey coevolve in an escalating cycle of complexity. Biologists have named this idea the Red Queen Principle after Lewis Carroll’s Red Queen, who explained to Alice, “Now, here, you see, it takes all the running you can do, just to keep in the same place.”
Like contests between predators and prey, wars between hosts and parasites initiate escalating arms races that require extravagant, harmful expenditures and create extraordinarily complex weapons and defenses. Just as political powers sometimes put more and more of their energies into weaponry and defense to keep from being dominated by opponents, hosts and parasites must both evolve as fast as they can to maintain their current levels of adaptation. There comes a point where the expense of an arms race is so great that the organism, political or biological, is hard put to meet other basic needs, but the cost of losing it is so great that enormous expenses may nonetheless be maintained. We are in a relentless all-out struggle with our pathogens, and no agreeable accommodation can ever be reached.
The relationships between hosts and parasites are so competitive, wasteful, and ruthlessly destructive that arms-race terminology offers an entirely appropriate framework for describing them. The rest of this chapter explains this point of view, but for an introduction, just try to imagine the magnitude of the personal tragedy that infectious agents have caused throughout human history, until just a few decades ago. The mother of one of the authors (Williams) was orphaned at age nine by meningitis. He has a sister whose best friend died suddenly of acute appendicitis in fourth grade. Our microscopic enemies take no account of individual merit or importance. Shortly before Calvin Coolidge succeeded to the presidency of the United States, his sixteen-year-old son got a blister on his foot while playing tennis but bravely went on playing. The blister broke open and became infected, and in two weeks the boy was dead. As a result, the president of the United States was an ineffective emotional cripple (as even his admirers concede) throughout the ensuing campaign and his one term in office.
The analogy between international arms races and host-parasite coevolution is not exact. The Pentagon can plan new weapons on the drawing board and then try out models and prototypes. It has the benefit of rational planning, fresh starts, and trial-and-error tinkering. In evolution, there are no think tanks systematically devising ways of putting scientific knowledge to new destructive or defensive uses. No plans contribute to evolution, and there can be no fresh starts. Evolution consists entirely of trial-and-error tinkering. The slightly different variants of every generation compete in the game of life. Some achieve a higher reproductive output than others, and the population averages shift slightly in their direction. The process is slow and unguided—in some ways misguided—but there is no limit to the precision and complexity of adaptation that the Darwinian process can generate.
PAST VERSUS CURRENT EVOLUTION
Many microbiologists incorrectly assume that hosts and their pathogens are usually in a state of slow evolutionary change toward some optimal future state, usually of active cooperation. This is a grossly unrealistic idea. Both pathogens and hosts must normally maintain close-to-stable equilibria by making trade-offs between competing values, such as growth rates and defensive activities. At equilibrium, a unit of improvement of one adaptation would require more than one unit of loss of another. A leaner rabbit might run faster, but at some point the benefit of still greater speed would not be worth the added risk of starvation. Likewise, our fever response is presumably optimized, at least for historically normal conditions. Higher and more frequent fever would make us less vulnerable to pathogens but would be more than counterbalanced by the costs of tissue damage and nutrient depletion. This will be true as long as the environment stays constant. If circumstances change, some of the optima for both host and pathogen will likely change. If bacterial pathogens are artificially kept in check for many generations, this may select for a decreased fever response, but if our technology fails and we become vulnerable again, we might recover a heightened fever response.
In all of this book’s other chapters we deal mainly with features of human biology establis
hed by long-term historical processes. In the present chapter we will discuss evolutionary changes that can occur within the next year, or perhaps maybe even next week. Because pathogens reproduce so rapidly, they also evolve rapidly.
Some of our defenses against disease, such as sickle cell hemoglobin, have evolved markedly in the last ten thousand years, during which we have had perhaps three hundred generations. The species as a whole has evolved significantly higher resistance to a few epidemic diseases such as smallpox and tuberculosis in the last few centuries, perhaps a dozen generations. Compare this to a bacterium’s three hundred generations in a week or two and the even faster reproduction of a virus. Bacteria can evolve as much in a day as we can in a thousand years, and this gives us a grossly unfair handicap in the arms race. We cannot evolve fast enough to escape from microorganisms. Instead, an individual must counter a pathogen’s evolutionary changes by altering the ratios of its various kinds of antibody-producing cells. Fortunately, the number and diversity of these chemical weapons factories are enormous and at least partly compensate for our pathogens’ great evolutionary advantage.
From an immunological perspective, an epidemic may change a human population dramatically. Those individuals who have contracted a disease and recovered will likely be immune to reinfection because they harbor vastly increased concentrations of the lymphocytes that make the antibodies that are most destructive of that particular pathogen. Adult immunity to childhood diseases such as mumps depends not on changing human gene pools but on changing the concentrations of different kinds of antibodies within each individual.
Small size gives our pathogens another advantage: their enormous numbers. Each of us carries around (mostly in our digestive and respiratory systems) more bacterial cells than there are people on Earth. These enormous numbers mean that even improbable sorts of mutations will occur with appreciable frequency and that any mutant bacterial strain with even the most minute advantage over the others will soon prevail numerically. We can expect our pathogens’ quantitative characteristics to evolve rapidly to whatever values are optimal for present circumstances.
In some catastrophic epidemics, a human population can evolve a higher level of resistance to an infectious disease in mere months. When Europeans first arrived in the New World, for example, some European diseases quickly killed as much as 90 percent of a Native American community in a short time. If the Native Americans’ vulnerability had had any genetic basis, the genes of the lucky few who survived the epidemic would have become proportionately more frequent, and we could say that the population, in this limited sense, evolved a higher resistance. This is an extreme example. More often, a human gene pool will be little changed by an epidemic, while the pathogen’s features may evolve dramatically.
BACTERIAL RESISTANCE TO ANTIBIOTICS
Perhaps the greatest medical advance of this century, and one of the greatest of all time, was the discovery that toxins produced by fungi could kill the bacteria that cause human disease. While arsenic compounds had been used for syphilis since Paul Ehrlich introduced them in 1910, the antibiotic era did not really begin until Alexander Fleming noted one day in 1929 that bacteria in his petri dishes would not grow properly in the vicinity of contaminating colonies of the mold Penicillium. Why should this have been? Why did the most effective antibiotics come from molds? Antibiotics are chemical warfare agents that evolved in fungi and bacteria to protect them from pathogens and competitors. They were shaped by millions of years of trial-and-error selection to exploit the special vulnerabilities of bacteria but to be nontoxic to the fungi.
A wide variety of fungal and bacterial products that are safe for most people can devastate the bacteria that cause tuberculosis, pneumonia, and many other infections. For several decades now, these antibiotics have given economically advanced societies a golden age of relief from bacterial disease. A combination of public health measures and antibiotics made the death rates from infectious disease fall so rapidly that in 1969 the Surgeon General of the United States felt justified in announcing that it was “time to close the book on infectious disease.”
Like other golden ages, this one may be short-lived. Dangerous bacteria, most notably those that cause tuberculosis and gonorrhea, are now more difficult to control with antibiotics than they were ten or twenty years ago. Bacteria have been evolving defenses against antibiotics just as surely as they have been evolving defenses against our natural weaponry and that of fungi throughout their evolutionary history. As Mitchell Cohen of the Centers for Disease Control and Prevention put it recently, “Such issues have raised the concern that we may be approaching the post-antimicrobial era.”
Indeed we may. Consider staphylococcal bacteria, the most common cause of wound infection. In 1941, all such bacteria were vulnerable to penicillin. By 1944, some strains had already evolved to make enzymes that could break down penicillin. Today, 95 percent of staphylococcus strains show some resistance to penicillin. In the 1950s, an artificial penicillin, methicillin, was developed that could kill these organisms, but the bacteria soon evolved ways around this as well, and still new drugs needed to be produced. The drug ciprofloxacin raised great hopes when it was introduced in the mid-1980s, but 80 percent of staphylococcus strains in New York City are now resistant to it. In an Oregon Veterans’ Administration hospital, the rate of resistance went from less than 5 percent to over 80 percent in a single year.
In the 1960s, most cases of gonorrhea were easy to control with penicillin, and even the resistant strains responded to ampicillin. Now 75 percent of gonococcal strains make enzymes that inactivate ampicillin. Some of these changes were apparently a result of standard chromosomal mutation and selection, but bacteria have another evolutionary trick. They are themselves infected by tiny rings of DNA called plasmids, which occasionally leave a part of their DNA behind as a new part of the bacterial genome. In 1976, it was discovered that the bacteria that cause gonorrhea had gotten the genes that code for penicillin-destroying enzymes via plasmids from Escherichia coli, bacteria that normally live in the human gut, so that now 90 percent of the gonorrheal bacteria in Thailand and the Philippines have become resistant. Similarly, the gene that caused antibiotic resistance in a strain of Salmonella flexneri that caused a 1983 outbreak of severe diarrhea on a Hopi Indian reservation was traced back to a woman who had been taking long-term antibiotics to suppress an E. coli urinary tract infection.
The list of threats we face from antibiotic-resistant bacteria is long and frightening. A plasmid-mediated ability to prevent binding of erythromycin has made over 20 percent of pneumococcal bacteria resistant to treatment with that drug in France. Some strains of the cholera now threatening thousands in South America are resistant to all five previously effective drugs. Amoxicillin is no longer effective against 30 to 50 percent of pathogenic E. coli. It appears that we are indeed running, together with the Red Queen, as fast as we can just to stay in the same place.
Perhaps most frightening of all, one third of all cases of tuberculosis in New York City are caused by tuberculosis bacilli resistant to one antibiotic, while 3 percent of new cases and 7 percent of recurrent cases are resistant to two or more antibiotics. People with tuberculosis resistant to multiple drugs have about a 50 percent chance of survival. This is about the same as before antibiotics were invented! Tuberculosis is still the most common cause of death from infection in developing countries, causing 26 percent of avoidable adult deaths and 6.7 percent of all deaths. TB rates in the United States fell steadily until 1985 but have increased 18 percent since then. About half of these cases resulted from impaired immune function in people with AIDS, the rest from increased opportunity for contagion and drug-resistant pathogens.
Increasing tolerance to antibiotics is the most widely known and appreciated kind of pathogen evolution. Since their discovery in the 1950s, an enormous number of studies have established many medically important conclusions:
1. Bacterial resistance to antibiotics arises not by the gradual devel
opment of tolerance by individual bacteria but by rare gene mutations or new genes introduced by plasmids.
2. Gene mutations can be transmitted by plasmid infection or other processes to different species of bacteria.
3. The presence of an antibiotic causes the initially rare mutant strain to increase and gradually replace the ancestral type.
4. If the antibiotic is removed, ancestral strains slowly replace the resistant forms.
5. Mutations within a resistant strain can confer still greater resistance, so that increasing the dose of an antibiotic may be effective only temporarily.
6. Low concentrations of an antibiotic, which may retard bacterial growth only slightly, will eventually select for strains that resist the slight retardation.
7. Mutations that confer still higher levels of resistance arise in such partially adapted strains more often than in the original nonresistant strain.
8. Resistance to one antibiotic may confer resistance to another, especially if the two are chemically related.
Why We Get Sick Page 7
