Mutations and Malaria: Pauling’s Adventure in Genetics

Pastel drawing of Hemoglobin at 100 angstroms, 1964.

During the 1940s, Pauling had established sickle-cell anemia as a molecular disease, a pioneering concept that synthesized biology and chemistry in a revolutionary manner. Other interests had pulled him away from this important work, however, for the better part of a decade.

Then, in the early 1960s, he was introduced to research suggesting that rates of malaria infection in areas with a high rate of sickle-cell anemia were greatly reduced. On top of this existing research, Pauling also came across a reference to a particularly interesting African legend regarding the origin of malaria resistance. Intrigued, he decided to dig a little deeper and, before long, he had dedicated a small portion of his lab to the problem.

Early in his research, Pauling found that the protozoan parasites responsible for malaria were not able to penetrate and replicate in sickled blood cells — e.g, cells containing deformed hemoglobin. Even more interesting, Pauling discovered that individuals with only one sickle-cell allele did not suffer from the effects of sickle-cell anemia but were still highly resistant to the malaria disease.

By examining these findings, Pauling developed a set of basic rules explaining the sickle-cell and malaria interactions. They are as follows:

1. Individuals with only normal hemoglobin do not possess the deformed hemoglobin molecules present in individuals possessing either one or two sickle-cell alleles. As a result, these individuals are not resistant to malaria.
2. Those with the homozygous recessive sickle-cell trait suffer from sickled blood cells, resulting in a variety of health complications including stroke, ulcers, bacterial bone infection, kidney failure, and heart problems. Victims of the dominant form of sickle-cell anemia have a significantly shorter lifespan than the average human, often dying in infancy. Nevertheless, these individuals are not afflicted by the malaria disease.
3. Other individuals are heterozygous for the sickle-cell trait, meaning that they experience some sickling of the blood cells, but enough of their blood cells appear normal that they are able to survive without experiencing the health difficulties associated with sickle-cell anemia. Like those with the full sickle-cell anemia disease, these individuals enjoy significant resistance to the malarial disease.

Pauling stated that the human populations inhabiting malarial zones in Central Africa were becoming predominantly comprised of heterozygotes. He explained that an individual homozygous recessive for the sickle-cell trait would probably die before reaching sexual maturity, therefore not producing any children with the sickle-cell disease. Those without the sickle-cell trait would be vulnerable to malaria. In malarial regions, this group would have a high mortality rate, many of them dying before reproducing. The third group, those with only one sickle-cell allele, does not suffer from the effects of full sickle-anemia and are immune to malaria. As a result, these individuals are best suited to malarial regions and are able to procreate, giving birth to more heterozygotes who can, in turn, continue the genetic trend.

The sickle-cell trait is a hereditary disease, passed from parent to child in the Mendelian fashion. Each parent provides the child with one of the two alleles which will determine whether the child will have normal or sickled blood. Two individuals with sickle-cell anemia will invariably produce children with sickle-cell anemia. A pair in which one parent has sickle-cell anemia and the other is a carrier (meaning they have one trait rather than two) will have a 50% chance of producing a child with sickle-cell anemia and a 50% chance of producing a child with only one sickle-cell allele. A couple in which both parents carry only one sickle-cell allele will have a 25% chance of producing a child with sickle-cell anemia, a 25% chance of producing a child without the sickle-cell trait, and a 50% chance of producing a child with only one sickle-cell allele.

The following series of Punnett squares demonstrates the transfer of alleles in the case of sickle-cell anemia:

Sickle-Cell Anemia Punnett Square

Based on this thinking, Pauling argued that only the people with one sickle-cell allele would live to have children, approximately 50% of which would be born with one sickle-cell allele. He argued that this trend could continue indefinitely, probably until a mutation eliminated the sickle-cell disease entirely, leaving all peoples in malarial zones homozygous for an anti-malarial gene.

Listen: Pauling on the effect of sickle cell disease on the spread of malaria

With his theory firmly in place, Pauling turned his attention to sickle-cell anemia in non-malarial zones. Pauling was primarily concerned with the presence of sickle-cell anemia in the African American population of the southeastern United States. Because malaria is not endemic to the southern U.S., Pauling feared that a positive mutation was unlikely to occur, and the sickle cell mutation was not being removed from the gene pool as quickly as new, harmful mutations were occurring. As a result, the number of individuals suffering from sickle-cell anemia could only continue to increase.

In order to counteract this trend, Pauling spoke out in support of eugenics as a means of controlling and gradually diminishing the presence of sickle-cell anemia in the United States.

In the 1960s and 1970s, Pauling made headlines by giving talks on the subject. He was introducing the concept of beneficial mutations to a public not necessarily comfortable with certain implications of the phenomena. The humanitarian components of his efforts earned him praise from various medical groups, though his advocacy of eugenics created some concern among politicians, religious conservatives, and secular ethicists alike.

For more information on Pauling’s work with sickle-cell anemia and malaria, visit It’s in the Blood or take a look at the OSU Special Collections homepage.

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