The sea nymph Idothea told the lost and desperate Menelaus what he needed to do to get back home to Sparta. Menelaus would have to force the instructions out of her father, the sea god Proteus. But Idothea warned Menelaus that the encounter would be challenging. Proteus would change his form to avoid being controlled. At one moment he might be a serpent, at another a leopard or a wild boar. If Menelaus could avoid being deterred by any of these forms, the sea god would eventually transform himself into a benign cooperative shape. By anticipating Proteus’ changeability and developing a strategy for coping with it, Menelaus could control his adversary and resolve his predicament.
This allegory is illustrative of the way we must face the problem of infectious disease. Many once-devastating infectious diseases have been controlled so effectively that they are no longer a problem for most of the world’s societies. Smallpox, diphtheria, polio, typhus, and measles are either no longer a problem or a problem only in areas in which the infrastructure and economic support are insufficient to implement proven solutions. But these diseases are the easy adversaries, the ones that could be controlled by identifying their Achilles’ heel and attacking it with a primitive weapon. For some pathogens the Achilles’ heel was vulnerability to the immunity generated from natural infection and from vaccines, a vulnerability that is attributable partly to a low potential for change. Smallpox, for example, had such a low potential for generating variation that a primitive vaccine made from a distantly related virus could rid it from the human population. We are left with the wily adversaries, protean opponents that change in response to our attacks.
HIV is one of these protean opponents. Its high mutation rate and potential for recombination allow it to wriggle free of the control we try to impose through our immune system and antiviral drugs. We have not even gotten close to controlling it with a vaccine.
Malaria is another protean opponent. Its flexibility arises from its sexual reproduction. The malaria organism’s version of sperm and egg come together in the mosquito, reshuffling the genetic deck before each round of human infection. If several different genetic instructions are particularly useful to a malaria parasite, they can come together by way of this shuffling so that one organism can put together a hand combining the best that the trillions of parasites in a region have to offer. It might be a combination of instructions for countering one or more commonly used antimalarial drugs, or new versions of proteins that allow the organism to evade the immunity that has been acquired by the people in the region.
Ever since the antimalaria campaign fell apart in the 1960s, master planners have been dangling the prospects of an effective vaccine that could eradicate malaria. It is a desperate hope of last resort. Humans have never controlled a sexually reproducing protozoal parasite by vaccination. Vaccination against viral and bacterial diseases has a long record of success, but this success tells us little about the possibilities of controlling a sexually reproducing protozoan. Far from providing long-term control, antiprotozoal vaccines have not yet worked well even in the short run. For malaria control, working in the short run will be the easy part of the task because it will involve stimulation of the protection that already occurs among people who have acquired resistance from previous infections. If efforts at vaccine development continue, a vaccine that is moderately effective in the short run will probably be developed. But after its introduction, such a vaccine is bound to become steadily less effective as the variants that are not suppressed by the vaccine take over.
Why the blinders? Part of the reason is that immunological suppression of malaria occurs among people who live in malaria-infested areas. If these people are resistant, the thinking goes, then we should be able to generate similar resistance with the right vaccine. This reasoning focuses on the full half of the glass: a vaccine probably could be developed that would provide some degree of protection against malaria. The empty half of the glass, however, tends to be ignored: in spite of these moderately effective immunological responses and the genetic defenses that are present in people in endemic areas (such as alleles for sickle-cell anemia), the “resistant” people still develop malaria. As with HIV, there are already variants in the pathogen population that are not adequately controlled by the immunological response. Even without any novel variants arising, the existing variation suggests that vaccination would be at best moderately successful. As new variants arise and spread, the control will weaken further.
But desperation is another important cause of the reliance on the vaccine option. Researchers do not know where else to turn. They are convinced that the solution will come from some high-tech fix, and the only high-tech fixes they can think of involve the use of insecticides, antimalarial drugs, and vaccines. Insecticides cause evolution of resistance in insects; antimalarials cause evolution of resistance in malarial parasites. Vaccines will probably cause resistance to vaccines, but this barrier has not yet been encountered—so, the logic goes, let’s try, and hope that it does not happen. In 1991, after several decades of research directed toward malaria vaccines, the London School of Hygiene and Tropical Medicine published an overview of approaches entitled Malaria: Waiting for the Vaccine. A decade later we are still waiting. Malariologist Kamini Mendis entitled the final chapter of the volume “Malaria Vaccine Research—A Game of Chess.” A good metaphor. He did not mention, however, that human immune systems have never won such an immunological game of chess, whereas malaria has been honing its game against our immune systems for at least many thousands of years, and probably since before there were humans.
There is another option. Rather than trying to beat the master at his own game, change the game, and change the adversary. That is what we have done for all our domesticated animals and plants. Instead of being stymied by evolutionary responses to control strategies, incorporate the evolutionary responses into the strategies. For malaria, as well as for every other infectious scourge, understanding the reasons for the evolution of harmfulness and benignity points to interventions that will give people something that they want in the short run while making the pathogens evolve toward benignity in the long run.
Modern medicine uses a three-pronged method to control infection, each of which—hygiene, antibiotics, and vaccines—can be used with an eye toward evolutionary control. The evolutionary framework is like a handle that transforms the three prongs into a more effective tool, a pitchfork that can be used not just for attacking microbial enemies but also for giving them evolutionary pricks in the butt to make them evolve down a trajectory favorable to us.
That is how we have most successfully dealt with conflicts of interest between us and the animals and plants we depend on, and in fact we have already unknowingly applied the method to many pathogens to make them work for us. The polioviruses that have been attenuated in live vaccines, for example, are domesticated viruses. That kind of domestication is fairly easy to control because it occurs in dishes, tubes, and flasks. An experimenter can pick and choose organisms with desirable characteristics for the next generation. But the health sciences have been particularly unimaginative in restricting their efforts at domestication to the lab.
Selective breeding and genetic engineering of domestic animals and plants is now a major industry, but the first stages of domestication probably resulted from people doing things they wanted to do in the short term without any thought of long-term consequences; these shortsighted activities then changed the organisms people were interacting with over the long term. People who carried different wild seeds in pots for growing the following year would favor seeds that had characteristics that would allow them to keep well in pots. People who found a wolf pup cute and cuddly were more likely to take it home and became attached to it, and so on down the line, as that lineage of wolf evolved into a lineage of dog.
There is a lesson to be learned from the history of domestication. People acting in their short-term interest can be powerful forces shaping the organisms with which they interact. If we want to domesticate pathogens without taking them into the lab, we will probably be most successful if we nudge people down paths they would like to go in the short run. If we nudge ourselves in the right direction, the evolution of our pathogens will follow.