One of the more fascinating aspects of evolution is the continuous “battle of the species”; one species trying to fend off the attack of another, parasitic species. It is a classic warfare of measure/countermeasure, not unlike modern warfare. But unlike human warfare, a successful parasite is not the one that kills its host—that would spell the demise of the parasite; that would be self-defeating, won’t it? Success is defined as the capacity to live off the host and efficiently spread to other individuals. The host, on the other hand, is successful if it can avoid being killed by the attack and keep the attacker in check. And so, we can see a battle of adaptations: A parasite honing its “skills” so as to attack, but not kill, just colonize; the host, adapting to the presence of the parasite but keeping the damage to a minimum. You might say that both warring species arrived at an arrangement of cohabitation, or détente.


How can a species adapt?

This answer is natural selection. Again, the example of warfare is most instructive. Imagine an enemy invading another country. As long as the invader can enjoy the abundant food and shelter the country provides, its chances of conquering this country are quite good. And if it doesn’t kill off the farmers who produce the food, it will continue to thrive in the conquered country. The British Empire is a perfect example of such “enlightened” colonization. But consider Napoleon in Russia or Hitler in the USSR. The invaders’ brutality, on the one hand, and the response of “scorched earth” strategy, on the other, were ultimately responsible for the ignominious defeat of the invaders. Likewise, HIV or the Ebola virus are pretty lousy parasites: They kill their hosts. On the other hand, parasites like leeches are quite successful; nobody dies. The host may become weakened, and the leach “knows” to fall off when it is engorged with blood—but both sides survive to live another day.



Now here is a truly interesting twist on the war between the species. Back to our warfare analogy. What if the conqueror conscripts all able-bodied farmers to work the land to supply it with food, but spares the infirm? Wouldn’t that favor the survival of the infirm? If the conditions of labor under the conqueror are especially harsh and even deadly, then, of course, the spared sick people would constitute an increasing part of the population. So here is selection, albeit not quite natural, in action. Similarly, what would happen if a parasite infected a person with some genetic mutation that affected the parasite’s ability to survive? Obviously, the parasite would not survive, and the mutation, albeit deleterious, would confer a survival advantage on the person who carries it. And this is how a parasite that evolved to infect humans, can, in turn, cause a change in the human genome. If the infection is deadly enough, the individuals who possess the mutation would slowly constitute an increasing proportion of the population.


Malaria, the quintessential human parasite

Malaria, a tremendously successful pathogen that is responsible for more than 300 million cases and 1 million deaths annually, has had a large impact on the shape of the human genome. Malaria-selected mutations in human genes promote survival in areas where malaria is endemic. The parasite’s substantive effect on the human genome is due to its high prevalence in areas where it is endemic and its long history of co-evolution with humans. Stop and think for a moment: We all came out of Africa at one point or another. So, this lowly parasite had a hand in shaping our genome! Indeed, not only this one. We can find the fingerprints of hundreds of viruses and bacteria in our genome. What a perfect demonstration of the influence of the environment on our genes.

Several mutations that confer resistance to malaria have been identified. Interestingly, all of them interfere with the energy metabolism or with the synthesis of proteins of red blood cells. Why is this particular cell so important? Because the malaria parasite (Plasmodium falciparum) spends a phase of its life cycle in red blood cells, before moving on to the liver. Unsurprisingly, these mutations are prevalent only in areas where malaria is endemic. For instance, sickle cell anemia is prevalent in Africans and African Americans. Two other conditions, known as α and β Thalassemias are most prevalent in Africans and Mediterraneans. And yet another, known as G6PD deficiency, is prevalent among Jews and Saudis (could that form a basis for understanding between the warring neighbors?). All of these mutations inflict pain and misery on its carriers; but there is a silver lining—they are all resistant to malaria.

A recent paper in the New England Journal of Medicine added another mutation to the roster: An enzyme known as PK (pyruvate kinase) which is important in, you guessed it, the energy metabolism of the red blood cell. The paper provides us with additional insight into the subtleties of “the war of the species”. We have two copies of each gene (each copy is known as an allele). If the mutation is in only one allele (the other is non-mutated, or wild-type), the individual is quite healthy and acquires moderate resistance to the parasite. But if the mutation is in both alleles, the resistance to malaria is absolute—but the person suffers from severe anemia. A medical case of “no free lunch”.

The subtleties of the struggle between invader and victim don’t end there. In addition to mutations affecting red blood cells, we have an immune response that jumps into action when confronted with the foreign invader. Furthermore, the immune response can differ between individuals in the variety of mechanisms that are employed (such as antibodies, blood cells called macrophages, other blood cells called lymphocytes). And this is just a small sampling of the variability (called polymorphism) between individuals. But the invader doesn’t just give up and goes home. The malaria parasite evolved as a response to human polymorphism marked genetic diversity (polymorphism) of its own, which allows it to maximally adapt to the various defenses the host throws up against it, and continue transmission. As you can appreciate, co-evolution is an unending battle, where each side deploys new weapons, only to be countered but even newer weapons.


Why is it important?

Does anybody require a more compelling demonstration of evolution and natural selection in action? Or for that matter, let’s not forget the measure/countermeasure war between bacteria and antibiotics. But let’s not get sidetracked by the bizarre politics of science in America. The rest of the world has accepted natural selection as a fact of life as we know it. I am sure we’ll catch up one day.

Why is the study of pathogen-selected host polymorphisms useful? Because it provides insight into naturally occurring mechanisms of host defense, which could be used to develop therapeutic agents to combat disease. The fight against malaria has been long and frustrating. Attempts to develop vaccines against the malaria organism all ended up in failure. A deeper understanding of the rules of war between us and the parasite, the measures and countermeasures employed by the combatants, will give us a clue where the vulnerabilities of the enemy lie and allow us to defeat it.

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.


  1. This is a nice article I like it. Am amedical student and this article has really helped me alot in supplimenting my research

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