Sickle Cell Disease (SCD)


Recorded History in the United States

sickle cell disease history
Cancelled Stamp From The United States Featuring An Appeal For Early Testing For Sickle Cell. Credit: Getty Images

The first case of sickle cell disease (SCD) in the United States was described in 1904 when Walter Clement Noel, a 20-year-old dental student from Grenada, sought care for anemia at Chicago Presbyterian Hospital where he met Dr. James B. Herrick (1861-1954), a cardiologist and professor of medicine. Noel experienced recurrent episodes of “muscular rheumatism” and “bilious attacks” over a period of 3 years.1 

Dr. Herrick assigned this case to his intern, Dr. Ernest E. Irons (1877-1959), who performed the initial blood work on Noel, observed the unusual sickle-shaped red blood cells in the sample under the microscope, and informed his attending physician about the odd-shaped cells. Dr. Herrick then took an interest in the case given the unknown nature of this novel disease.2,3  

In November 1910, he published the first documented case study of SCD, titled “Peculiar Elongated and Sickle-Shaped Red Blood Corpuscles in a Case of Severe Anemia,” in the Archives of Internal Medicine (Chicago).4 Noel received treatment from Dr. Irons for 3 years prior to graduating and returning to Grenada to practice dentistry. Noel died in 1916 from pneumonia.5 

The disease name, sickle cell anemia, was not coined until 1922 by Vernon Mason.1

Recorded History in Africa

Although Herrick described the first known case in the United States, SCD has existed for generations in families of African and Mediterranean descent.1 It was described in local African medical literature around the 1870s with the phrase “ogbanjes,” which translates into “children who come and go” due to the high mortality rate of infants with this disease. One Ghanian family traced the inherited disease back to 1670.1,5

History of Disease Pathophysiology

In 1927, Hahn and Gillespie made the groundbreaking discovery that red blood cells sickled with the removal of oxygen in a cell suspension saturated with carbon dioxide. They observed that this sickling characteristic could occur in the absence of the disease when they realized that patients with SCD had relatives who did not have the disease but still had the sickling characteristic. This later became identified as “sickle trait.”3,6

In the late 1940s and early 1950s, ongoing research clarified the pathophysiology of SCD. In 1949, 2 publications independently described the autosomal recessive mode of inheritance of SCD. A military physician, Col. E. A. Beet, working in Portuguese East Africa (now Mozambique) published his article in an African medical journal. Dr. James V. Neel, a physician working at the University of Michigan as chair and founder of the Department of Human Genetics, authored the other article, published in the American journal Science. These physicians detailed how individuals with “sickle trait” were heterozygous carriers of the gene variant along with a normal gene such that they did not have the disease, while the disease manifested in individuals with 2 copies of the variant gene.3 

In 1951, Dr. Linus Pauling, who won the Nobel Prize for his work in chemistry, and his colleague, Dr. Harvey Itano, discovered the differing chemical structure of oxygen-carrying hemoglobin in the red blood cells of individuals with SCD. With this discovery, SCD became the first identified disease of thousands that are caused by dysfunctional proteins due to their abnormal molecular structure.3

In 1956, Dr. Vernon Ingram described in greater detail the exact structural alteration found in the hemoglobin protein, with the substitution of valine for glutamic acid in the sixth amino acid in beta globin.7 He has since published updated research in 2004 in Genetics about this molecular abnormality as the cause of SCD.8

In the early 1970s, Dr. Charles F. Whitten became a significant pioneer for SCD awareness in medical education programs. His advocacy efforts also contributed to the foundation of the Sickle Cell Disease Associations of America (SCDAA).5

Disease History

Currently, 2 models describing the origin of the SCD mutation exist – a multicentric model and a unicentric model.9 Several sources detail a multicentric model in which 4 independent genetic mutations (3 in Africa and 1 in either Saudi Arabia or central India) occurred over 70,000 to 150,000 years ago, spanning 3000 to 6000 generations, and these 4 original genetic events resulted in the inheritance of the sickle cell gene.1,5 

The most recent, universally adopted evidence points to the unicentric model in which the sickle cell mutation occurred in a single individual in western Africa, most likely in the rainforest of present-day Cameroon.10 All 5 haplotype variations of the SCD gene are present in Cameroon and Egypt, which indicate a longer presence in these regions.10 By applying whole-genome sequencing, researchers traced the single mutation back 259 generations, an estimated 7300 years ago, prior to the eastward and southward African Bantu migration (expansion), which occurred around 5000 years ago.9

Individuals with the sickle cell trait have a survival advantage, particularly in early childhood, against contracting or dying from falciparum malaria. Researchers have observed that if these individuals with sickle cell trait contract malaria, they show decreased parasite counts. Thus, regions with a history of malaria demonstrate increased prevalence of the sickle cell trait, reaching levels as high as 40% in sub-Saharan African, eastern Saudi Arabia, and central India.11

References

  1. About Sickle Cell Association St Louis. Sickle Cell Association. Accessed November 4, 2021.
  2. Savitt TL, Goldberg MF. Herrick’s 1910 case report of sickle cell anemia. The rest of the story. JAMA. 1989;261(2):266-271.
  3. Winter WP. A brief history of sickle cell disease. Howard University Hospital. Accessed November 4, 2021.
  4. Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. Arch Intern Med (Chic). 1910; VI(5):517-521. doi:10.1001/archinte.1910.00050330050003
  5. History of sickle cell. Sickle Cell Association Of New Jersey. Accessed November 4, 2021.
  6. Frenette PS, Atweh GF. Sickle cell disease: old discoveries, new concepts, and future promise. J Clin Invest. 2007;117(4):850-858. doi:10.1172/JCI30920
  7. 1956: cause of disease traced to alteration. National Human Genome Research Institute. Updated April 23, 2013. Accessed November 4, 2021.
  8. Ingram VM. Sickle-cell anemia hemoglobin: the molecular biology of the first “molecular disease”–the crucial importance of serendipity. Genetics. 2004;167(1):1-7. doi:10.1534/genetics.167.1.1
  9. Esoh K, Wonkam A. Evolutionary history of sickle-cell mutation: implications for global genetic medicine. Hum Mol Genet. 2021;30(R1):R119-R128. doi:10.1093/hmg/ddab004
  10. Shriner D, Rotimi CN. Whole-genome-sequence-based haplotypes reveal single origin of the sickle allele during the Holocene wet phase. Am J Hum Genet. 2018;102(4):547-556. doi:10.1016/j.ajhg.2018.02.003
  11. Serjeant GR. The natural history of sickle cell disease. Cold Spring Harb Perspect Med. 2013;3(10):a011783. doi:10.1101/cshperspect.a011783

Reviewed by Kyle Habet, MD, on 11/15/2021.

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