For most of the twentieth century, a poor grasp of natural selection and a tendency to pick and misinterpret specific examples led medical authorities to misunderstand the wide variation in virulence found among human diseases. The poor grasp of natural selection led them to presume that benign coexistence was always the best policy for parasites. The selective picking and misinterpreting of specific examples gave them a sense that their mistaken ideas were supported by the evidence.

Much reference was made, for example, to the high virulence of pathogens that were new to a host. A modern-day example is the Ebola virus, which often causes terrible destruction of tissues but tends not to spread to others in the community. True, the Ebola virus is poorly adapted to us. True, it recently entered humans and would probably be gentler to us if it had had a chance to adapt to us. But these truths do not lead to the conclusion that pathogens will generally evolve toward benignity as they adapt to their host. As I have suggested, a more careful application of evolutionary principles leads to the conclusion that some pathogens will evolve toward benignity and some will not, depending on the trade-offs inherent in the competition among pathogens to use hosts as food and to be transmitted to susceptible hosts. We can expect pathogens that are poorly adapted to us to range across the entire spectrum of virulence, with some being far more mild and others being far more harsh than they would be if they were well adapted. In fact, the overly mild ones should tend to be particularly well represented among poorly adapted pathogens because the immune system has to be able to protect against a tremendous variety of poorly adapted potential pathogens that are raining down on us with every walk in the woods, and every breath in a home. They may be organisms adapted to the cats, dogs, and mice that share our homes, or the fungi and bacteria that grow in the soil, in our bathtubs, or in our faucets, or those that are transmitted in our ventilating systems. If it were not for our immune systems, some of these organisms would turn our bodies to mush. But they have had little opportunity to adapt to us and are easily controlled by our immune systems, which have to be deft at defending against a tremendous array of organisms that would otherwise use us as food. When a few squeak by we notice them. Though such maladapted microbes may have been lucky enough to evade the immunological defenses, their lack of adaptation means that they lack a mechanism for finely regulating their use of the human food they have access to. The result is likely to ensue quickly, and can prove deadly, as with a case of Ebola. If we forget that there are vastly more maladapted microbes that never trouble us than maladapted microbes that do, we may mistakenly conclude that microbes as a rule either die out through overkill or evolve toward mildness, and, hence, that virulence is a state of maladaptation. Too many medical researchers have done just that.

This mistaken interpretation has been erroneously supported by evidence from an Australian campaign to eliminate rabbits. The rabbits were released in 1859 on a ranch in Victoria and quickly increased to such great numbers that they took over grazing land used by agricultural animals and natural wildlife. Australian grazing lands started to bear an uncanny resemblance to arctic tundra during a lemming boom—small mammals scurrying all over the place.

To control the rabbits, microbes were sought. The more lethal the microbes the better. The search led to the myxoma virus, which was not particularly harmful to its native South American rabbits, but killed almost all the Australian rabbits on which it was tested. When the virus was first introduced in the 1950s, it was tremendously effective, killing well over 95 percent of the rabbits it infected. But over the next few decades mortality dropped precipitously as a result of both reduced virulence of the virus and increased resistance in the rabbits. Mortality eventually stabilized at around 20 percent.

Those who believed that pathogens always evolved toward benignity quickly seized on this experience as supportive evidence. The rabbits would disagree. The virus generated by this evolutionary process is about as nasty to the rabbits as the smallpox virus was to us. In fact, the myxoma experience offers no evidence that microbes evolve to benignity. Rather it shows that a microbe chosen as a biological control agent on the basis of extreme lethality coevolved with its new host to a level of virulence that was lower, but nowhere near benignity. Being a

mosquito-borne pathogen, the myxoma virus equilibrated at a lethality that was consistent with the range of lethality among vector-borne pathogens of humans, though still on the virulent side of this range.

One of the most interesting points demonstrated by the myxoma experience is that evolutionary changes in virulence can occur very rapidly, over just a few decades. This point, together with some simple evolutionary logic, reveals the incoherence of the traditional argument that pathogens evolve toward benignity. Consider the persistence paradox: How does one explain the great variation in virulence that is present both within and among different kinds of pathogens? Advocates of universal evolution toward benignity were forced to conclude that

variations in virulence were just noise in the system. But if harmful pathogens are assumed to be at a disadvantage, they should vanish over relatively short periods of time, just as the most harmful myxoma viruses vanished over only a few decades. If the harmfulness resulted from variation in host susceptibility, the susceptible hosts should similarly vanish over time. Granted this time might be longer, but it should still mount up over generations, just as the reductions in the rabbits' susceptibility mounted up over a small number of rabbit generations. After many thousands of years of exposure to disease agents like smallpox and tuberculosis, one would expect the individuals who are resistant to the disease to make up the entire population.

The way natural selection actually works does not create this persistence paradox. The variation we observe in host susceptibility and pathogen virulence is simply the current stage in a long-running arms race, much like the arms race between antibiotic use and antibiotic resistance. But in this case the race is between the biological weaponry that our bodily defenses impose on pathogens and the pathogens' resistance to them. It is a race between our resistance to pathogens and pathogen resistance to us. Virulence continues because the race continues. As resistant humans become more numerous, pathogens that are not controlled by the human defenses are favored and they begin to prosper. In turn, new resistance mechanisms emerge in hosts.

Variations in the virulence of acute diseases are not just noise in the system. The differences in harmfulness are generally as large as one expects them to be on the basis of fundamental evolutionary principles. The evolutionary framework explains well the variations in virulent acute infectious diseases, and this is a respectable accomplishment because the standard acute infectious diseases make up a large proportion of the diseases that we care about. But the standard acute infectious diseases are not the most complicated of infectious diseases. Acute infectious diseases invade and battle with our defenses. If we are lucky, they are quickly repulsed and we acquire immunity. If we are unlucky, they kill or severely injure us. Whatever the result, the battle and its out-comes tend to be well denned and conspicuous. Our encounters with other microbial adversaries are not so easy to follow. These other microbes may hide out in our bodies for long periods of time and then rise up again at unexpected times, causing new and more horrific reincarnations.