Hektoen International

A Journal of Medical Humanities

Heterozygous advantage: How one deadly disease prevents another

Neal Krishna
Boston, Massachusetts, United States

An allegory of malaria. Process print after M. Sand. Wellcome Collection. CC BY 4.0.

Of all the genetic disorders to which man is known to be a victim, there is no other that presents an assemblage of problems and challenges quite comparable to sickle cell anemia. Because of its ubiquity, chronicity, and resistance to treatment, sickle cell anemia remains a malady whose mitigation and cure still elude physicians, researchers, and scientists.

While simple recessive genetic diseases arise from spontaneous mutation regularly (in fact, ~10 of 1000 births globally present with single-gene disease), most are quickly eliminated from the gene pool through natural selection.1 Sickle cell anemia, a prominent recessive genetic disease, is the anomaly. Having lasted for millennia and with a significantly higher prevalence in some regions of the world (~1 in 360, in parts of Africa), the disease sends scientists an ambiguous message.2 Also called sickle cell disease or SCD, sickle cell anemia was first brought to attention in 1910 in the United States by Walter Clement Noel, a young Caribbean dental student born in 1884.

Noel, who had traveled to the United States from Grenada, was suffering from pain, fatigue, and malaise, and consulted James B. Herrick, a renowned Chicago cardiologist. Dr. Herrick, initially uninterested, passed the case along to his resident Ernest Irons, who examined Noel’s blood under the microscope and described finding red blood cells “having the shape of a sickle.”3 Dr. Herrick, interest piqued, became interested in Noel’s medically unique case and published “Peculiar Elongated and Sickle-Shaped Red Blood Corpuscles in a Case of Severe Anemia” in the Archives of Internal Medicine the same year.4 Dr. Herrick gained international recognition and became known as the pioneer behind sickle cell anemia; however, no treatments had been developed for the disease, and the ramifications and mortality of sickle cell anemia remained unknown. Noel continued his dental training in Chicago and received care from Dr. Irons for two and a half years, after which he returned to Grenada to practice dentistry. He died nine years later.

Sickle cell anemia had existed for at least five thousand years previous to its identification by Dr. Herrick, and numerous African tribes have called the disease by their own name for centuries. The Ga, Faute, Ewe, and Twi tribes, respectively, referred to sickle cell anemia as chwechweechwe, nwiiwii, nuidudui, and ahotutuo.5 Reports also state that ancient Indian tribes had identified and termed sickle cell disease; it is likely that communication about sickle cell disease passed from Indian to African culture, or vice versa, during medieval and colonial times. A more general and widely used African term is ogbanjes, which translates to “children who come and go.” Families with children who are ogbanje would typically possess death-themed family names, implying that the family would undergo an unnaturally early death.6

Sickle cell anemia is pernicious and has latched onto the human species with remarkable stamina. For many years, scientists were utterly bewildered, because even despite the death of those afflicted with it, the alleles of the disease would remain prevalent in populations around the world. Sickle cell disease served as a conundrum, a contradiction of basic science reminding scientists that at face value, biology had no need to follow any logical pattern or rhyme.

By 2011, building off of data from 1985, a large body of evidence had formed showing an interesting phenomenon: in impoverished countries such as Africa, India, and Malaysia, outsiders tended to rapidly acquire malaria, commonly spread through infected mosquitoes of the Anopheles genus.7 While the parasite has become less common in the Western hemisphere, it remains prevalent in countries with sparsely developed infrastructure, causing symptoms of fever, fatigue, vomiting, and death. However, much to the fascination and confusion of scientists, the natives of underdeveloped countries who had a high prevalence of sickle cell anemia seemed virtually immune to the lethal mosquito-borne pathogen.8 Following this thrilling observation, and with hope for a cure for malaria, scientists across the world were prompted to study sickle cell anemia with newfound excitement.

What followed was a sort of moral quandary that probed the natural boundaries of treatment, suffering, and reproductive fitness. Dozens of studies aimed to study how the deleterious sickle cell allele could cause any benefit, and the answer was uniquely elegant. Due to its incomplete dominance, heterozygous sickle cell anemia produces a phenotype midway between those with the disease and those without. This incomplete phenotype, termed heterozygote advantage or balanced polymorphism, results in enough cellular distortion to prevent the plasmodium from effectively living within the cell.8 Since anemic symptoms do not wholly afflict the cell, the symptoms of sickle cell anemia are less pronounced—a small price to pay for malarial resistance, especially in areas where other means of prevention are scarce. While those with sickle cell anemia are typically at an extreme survival disadvantage, in regions of endemic malaria, the sickle cell trait remains the “selected for” genetic condition. The rise to a high frequency of the alleles that produce sickled red blood cells is one of the most dramatic examples of malaria’s selective pressure on humankind.9,10

The therapeutic implications of malarial genetic resistance were enormous. They remain so. However, as quickly as news of heterozygous advantage soared into headlines, it receded out of sight. Presently, scientists in the field work tirelessly to pioneer therapies to prevent and treat malaria, and we are fortunate to live during the rise of precision medicine, gene therapy, and novel antibiotics. While such “dream treatments” are incredibly valuable, it would be fallacious to declare that they are the only avenue of treatment worth examining. We must keep in mind that human evolution developed and maintained the heterozygous advantage of sickle cell anemia to organically prevent the acquisition of malaria; perhaps it would be advantageous to invest in the further study of such biological mechanisms.

From its discovery in 2011, the study of heterozygote advantage has been refined and expanded. Soon after the discovery of balanced polymorphism in sickle cell anemia, scientists discovered that the heterozygous phenotype in cystic fibrosis protects against diseases involving loss of body fluid, including cholera, typhoid, and tuberculosis.8 As we learn more about the human body and its natural systems of defense, it becomes increasingly vital that we devote energy toward studying the natural mysteries which surround our evolutionary defense mechanisms.

Heterozygote “advantage” exists in several conditions, but an astute observer may notice that when considering most industrialized countries, such an advantage is, at best, ineffectual. In nations like the United States or the United Kingdom, sickle cell anemia and cystic fibrosis have higher incidences than the conditions they protect against.11,12,13,14 Then, scientists reason, why invest money in keeping potentially deleterious alleles in the gene pool?

Evolution is dynamic, and organisms do not remain static for the risk of extinction. Organisms that rely on other living beings are a prime example of a population that must evolve to survive. Malaria parasites of the P. falciparum genus provide ample evidence of the maneuvers and counter-maneuvers in the battle between humans and malaria. In individuals with sickle cell anemia, an essential protein required for malarial reproduction, glucose-6-phosphate dehydrogenase, or G6PD, is often deficient. It is shocking but logical, then, that some varieties of P. falciparum have begun to produce their own G6PD enzyme to serve as a proxy in their host.7 Malaria’s cry for battle against the human body’s natural defenses practically begs for further study.

The Red Cross and World Health Organization have invested resources into studying heterozygote advantage, and actively encourages the development of immunohematology education.15 Organizations like these have made immense progress in studying hematological conditions and bringing solutions to countries with scarce or inaccessible therapies and resources. It is only with the efforts of international health organizations that we have been able to make significant progress in educating, developing, and treating the citizens of the world.

While sickle cell anemia and malaria are formidable conditions and will remain so for the foreseeable future, we are fortunate to have access to precision medicines, breakthrough therapies, and international health organizations to help guide the path to universal treatment. Our world, the vast and beautiful Earth, is home to fascinating mechanisms of disease and treatment in our endless battle to evolve and develop. We at the forefront of science will surely experience turmoil and revision before we encounter significant development, but when progress inevitably comes, it will pave the way for even more inspirational breakthroughs.


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  10. Tishkoff, S. A. “Haplotype Diversity and Linkage Disequilibrium at Human G6PD: Recent Origin of Alleles That Confer Malarial Resistance.” Science 293, no. 5529 (2001): 455–62. https://doi.org/10.1126/science.1061573.
  11. [“Data & Statistics on Sickle Cell Disease.” Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, October 21, 2019. https://www.cdc.gov/ncbddd/sicklecell/data.html.
  12. “CDC – Malaria – About Malaria.” Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, March 29, 2018. https://www.cdc.gov/malaria/about/index.html.
  13. Schraufnagel, Dean. Breathing in America: Diseases, Progress, and Hope. Ashland: American Thoracic Society, 2014.
  14. Newton, Anna, Katherine Heiman, Ann Schmitz, Tom Torok, Andria Apostolou, Heather Hanson, Prabhu Gounder, et al. “Cholera in United States Associated with Epidemic in Hispaniola.” Emerging Infectious Diseases 17, no. 11 (2011). https://doi.org/10.3201/eid1711.110808.
  15. Aldarweesh, Fatima A. “The Duffy Blood Group System.” Human Blood Group Systems, Immunohematology Journal of Blood Group Serology and Education American Red Cross, 2019. https://doi.org/10.5772/intechopen.89952.

NEAL KRISHNA is a freshman at the University of Connecticut, studying Physiology and Neurobiology, Creative Writing, and Pure Mathematics. At UConn, Neal is in the Special Program in Medicine, an eight-year BS/MD program, and is heavily involved as a student leader on campus. Originally from Boston, Massachusetts, Neal enjoys reading poetry, singing opera at the New England Conservatory of Music, and volunteering with the United States Coast Guard Auxiliary.

Winter 2020 



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