Sickle Cell Disease: History and Discovery

Table of Contents

1. African Knowledge Came First
2. Walter Clement Noel and the 1910 Herrick Report
3. Naming the Disease and the Early Decades
4. Pauling 1949: The First “Molecular Disease”
5. Ingram 1956–1957: One Amino Acid
6. The Malaria Link and Heterozygote Advantage
7. Konotey-Ahulu and the African Lineage
8. From Description to Treatment and Cure
9. Key Research Papers
10. Connections
11. Featured Videos

African Knowledge Came First

The history of sickle cell disease begins in Africa, not in a Western hospital. A 2025 review notes that in 1974 the Ghanaian physician and geneticist Felix I. D. Konotey-Ahulu documented traditional African names for the disease, recorded from different ethnic groups, and that among the Ga people of Ghana it was called chwechweechwe, a name referring to its pain crises; his work stressed that the disease was not new to African populations but had been recognized and described for centuries (Starlard-Davenport 2025). A 2026 review, citing the same 1974 work, gives chwechweechwe, nwiiwii and nuidudui as names used by Ghanaian peoples and dates recognition of the disease in West Africa as far back as the 1600s (Jacobs-McFarlane 2026).

The Yoruba term abiku and the Igbo term ogbanje belong to wider beliefs about children who fall ill, die young and are thought to return to the same family; reviews list both among the West African names under which the disease was described (Egesa 2022; Ikolo 2026). They are not simply old words for sickle cell disease. The Igbo of Nigeria hold that everyone is ogbanje, but “malevolent” ogbanje are described as chronically ill and caught in repeated cycles of birth, death and reincarnation. In a 2001 study of 100 children classified as malevolent ogbanje, the cultural descriptions matched the symptoms of sickle cell disease, and hemoglobin analysis found sickle cell disease in 70 of the 100 children (Nzewi 2001). The word is still in use: a 2024 qualitative study in Cameroon, Ghana and Tanzania recorded ogbanje (“one who comes and goes”) among the stigmatizing labels applied to people living with sickle cell disease (Munung 2024).

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Walter Clement Noel and the 1910 Herrick Report

The first description of sickle cell anemia in Western medical literature is credited to the Chicago physician James B. Herrick (Savitt 1989). The patient was Walter Clement Noel (1884–1916), born in Grenada, then a British colony. After undergraduate studies at Harrison College in Barbados, he sailed to New York in September 1904, developing a leg ulcer on the voyage, and went on to Chicago as a dental student at the Chicago College of Dental Surgery (Steensma 2010). In late November 1904 he developed respiratory problems that lasted more than a month and sought care at the Presbyterian Hospital in Chicago (Steensma 2010). Herrick's report lists cough and fever as his main complaints, along with weakness, dizziness and headache, and gives his first blood count as December 26, 1904 (Herrick 1910). The patient was examined in 1904; the case was published in 1910.

The first observation of the cells was made by Herrick's intern, Ernest E. Irons, who performed the blood smear and noted “many pear-shaped and elongated forms—some small” (Steensma 2010). Working from records in Chicago, Washington, DC, and Grenada, Savitt and Goldberg showed that Irons performed the blood work and alerted Herrick to the odd-looking cells, and that Noel continued to receive care from Irons for two and a half years (Savitt 1989). Herrick's own report says the patient was “never afterward under my professional care” but was seen twice by Herrick and several times by Irons, whose notes and blood examinations the report reproduces (Herrick 1910). Irons gave his case notes to Herrick at the end of his training, and Herrick presented the case at a national meeting in 1910 without crediting Irons (Steensma 2010).

Herrick's paper, “Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia,” appeared in the Archives of Internal Medicine in November 1910. It reached no diagnosis — “No conclusions can be drawn from this case. Not even a definite diagnosis can be made,” Herrick wrote — though he suggested that “some unrecognized change in the composition of the corpuscle itself” might be the cause (Herrick 1910). Noel graduated in 1907, returned to Grenada to practice dentistry in St George's, and died in May 1916 at the age of 32; his death certificate gives the cause as “asthenia from pneumonia” (Steensma 2010). On 7 February 2026 the Government of Grenada posthumously conferred on him the Knight Grand Cross of the Most Distinguished Order of the Nation (Ikolo 2026).

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Naming the Disease and the Early Decades

Herrick described the cells but did not name the disease. A few months after his report a second, similar case was described in rural Virginia, and the next clear case was not published for another five years; by the early 1920s enough experience had accumulated for V. R. Mason to name the illness “sickle cell anemia” (Steensma 2010), in a report published in JAMA on 14 October 1922 (Mason 1922). The sickle — the curved harvesting blade whose shape the deformed red cells resemble — became the name of the disease.

By the 1940s it was known that the red cells take on the sickle form when they are deoxygenated and are prevented from sickling by oxygen; the Harvard hematologist William B. Castle described this to Pauling at a dinner in 1945 (Eaton 2020). The inheritance pattern was worked out in the same period. The geneticist James V. Neel published “The inheritance of sickle cell anemia” in Science in 1949 (Neel 1949), and a 2025 review credits Neel and Ernest Beutler with showing, in the 1950s, that the disease follows an autosomal recessive pattern: it is expressed only in people who carry two copies of the sickle allele (HbSS), while carriers of one copy (HbAS, sickle cell trait) do not show the disease's symptoms but can pass the allele on (Dorneles 2025).

The distinction between disease and trait set up a central puzzle: if two copies of the gene cause a serious illness, why is the gene so common in the populations where it is found? The answer came from the study of malaria.

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Pauling 1949: The First “Molecular Disease”

The chemist Linus Pauling and his colleagues Harvey A. Itano, S. J. Singer and I. C. Wells published “Sickle Cell Anemia, a Molecular Disease” in Science on 25 November 1949 (Pauling 1949). From 1945 to 1949 Pauling and Itano had looked for a structural difference between normal hemoglobin (hemoglobin A) and sickle hemoglobin (hemoglobin S); sedimentation and diffusion, the structural tools then available, showed none. In 1948 Pauling learned from Arne Tiselius how to build an electrophoresis apparatus, which separates proteins by their electrical charge, and with it found the difference (Eaton 2020). A historian of the work describes the custom-made electrophoresis machine at the California Institute of Technology as the tool that revealed the chemical difference between the normal and abnormal hemoglobins (Gormley 2007).

The paper reported two main results: hemoglobin S is more positively charged than hemoglobin A, and a 50–50 mixture of the two gives an electrophoretic pattern very similar to the hemoglobin of the parents of patients. From these, Pauling concluded that sickle cell anemia is due to an abnormal hemoglobin molecule — a “molecular disease” — and that it follows a Mendelian pattern of inheritance rather than the dominant pattern that had been suggested. At the April 1950 meeting of the US National Academy of Sciences, Pauling effectively withdrew two of his four conclusions (the estimated charge difference and the inheritance conclusion), because no difference in charged amino acids could be detected with the technology of the time and hemoglobin S levels in sickle trait could be as low as 25%; later work confirmed all four (Eaton 2020).

A 2020 retrospective describes the paper as the one that “gave birth to what is now called molecular medicine” (Eaton 2020), and Pauling could call sickle cell anemia “the first molecular disease” (Steensma 2010). The next question was what, exactly, differed in the abnormal hemoglobin.

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Ingram 1956–1957: One Amino Acid

The answer came from the biochemist Vernon M. Ingram. Pauling's result showed that sickle hemoglobin differed in charge, but not where the difference lay. In 1956 Ingram reported “a specific chemical difference” between the globins of normal and sickle-cell hemoglobin (Ingram 1956), and in 1957 he identified the precise substitution (Ingram 1957; Ikolo 2026). He compared the two hemoglobins by a technique he called “fingerprinting,” set out in a 1958 paper (Ingram 1958).

The substitution is at position 6 of the beta-globin chain, where the amino acid glutamic acid is replaced by valine: one amino acid out of the 146 that make up the chain (Ikolo 2026). At the DNA level it is a single-letter change, GAG to GTG, at codon 6 of the HBB gene (Egesa 2022; Ikolo 2026).

In the swap, a hydrophobic (water-avoiding) valine replaces a hydrophilic (water-attracting) glutamic acid (Egesa 2022). Pauling had already reasoned that the change must lie on the surface of the molecule to cause aggregation, and that oxygenated and deoxygenated hemoglobin must differ in structure, since oxygenated hemoglobin S does not aggregate (Eaton 2020). When it gives up its oxygen, hemoglobin S polymerizes inside the red cell into rigid, crystal-like rods that deform the normally flexible cell into the sickle shape; the polymerization reverses when the cell is reoxygenated, but repeated episodes damage the red-cell membrane and cause hemolysis (Egesa 2022). The sickled cells restrict blood flow and oxygen delivery to tissues, leading to severe pain and organ damage (FDA, December 8, 2023).

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The Malaria Link and Heterozygote Advantage

Alongside the molecular story ran an evolutionary question: why is a gene that causes a serious disease in double dose common in sub-Saharan Africa, India, the Mediterranean and the Middle East (Jacobs-McFarlane 2026)? The “malaria hypothesis” was first proposed by the geneticist J. B. S. Haldane in 1949 to explain why thalassaemia was common in the Mediterranean region; at around the same time Anthony C. Allison and others suggested that selection by malaria might also explain the high frequency of hemoglobin S in malaria-endemic areas (Kariuki 2020).

In 1954 Allison published a study of the distribution of the sickle-cell trait in East Africa and elsewhere and its apparent relationship to the incidence of subtertian malaria (Allison 1954a), and the paper “Protection Afforded by Sickle-Cell Trait against Subtertian Malarial Infection” in the British Medical Journal (Allison 1954b). Allison later summarized the finding as the 1954 demonstration that sickle-cell heterozygotes have less severe Plasmodium falciparum infections than children with normal adult hemoglobin. The observation has been repeatedly confirmed, most recently by genome-wide association studies of severe falciparum malaria that identified the HBB locus as the major signal of association (Allison 2009).

The result is a classic case of heterozygote advantage. Sickle cell trait confers a significant survival advantage in regions of high malaria endemicity, and the distribution of the sickle allele correlates with the distribution of malaria (Egesa 2022), while people who inherit two copies have sickle cell disease. Among the inherited variants that protect against falciparum malaria, a 2020 review describes sickle cell trait (HbAS) as the most strongly protective (Kariuki 2020).

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Konotey-Ahulu and the African Lineage

The Ghanaian physician and geneticist Felix I. D. Konotey-Ahulu recorded the indigenous names for the disease in his 1974 work The Sickle Cell Diseases and stressed that the disease was not new to African populations (Starlard-Davenport 2025). He later wrote The Sickle Cell Disease Patient (Macmillan, 1991), a natural history drawn from a clinico-epidemiological study of 1,550 patients at the Korle Bu Hospital Sickle Cell Clinic (Konotey-Ahulu 2009; Ikolo 2026). In a 2009 personal historical perspective he described the British and Hungarian contributions to clinical genetics research in Ghana (Konotey-Ahulu 2009).

His work is a reminder that “discovery” in medicine is often the formal recording of something people already knew. The communities that named the illness chwechweechwe knew it long before laboratory science described its mechanism and its molecule; what twentieth-century science added was the mechanism, the molecule and, eventually, treatments.

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From Description to Treatment and Cure

For most of the twentieth century, understanding of the disease ran ahead of treatment. In a multicenter, randomized, double-blind trial published in 1986, children with sickle cell anemia under three years old received 125 mg of oral penicillin V or placebo twice daily. The trial was stopped 8 months early, after an average of 15 months, when the incidence of septicemia due to Streptococcus pneumoniae was 84% lower with penicillin (2 of 105 children vs. 13 of 110 with placebo); there were no deaths from pneumococcal septicemia with penicillin and three with placebo. The authors called for newborn screening so that children with sickle cell anemia could start penicillin by four months of age (Gaston 1986). The trial led to recommendations for universal newborn screening across the US; in recent years Europe, the UK and Canada have adopted newborn screening for sickle cell disease, and pilot programs have run in Africa, Brazil and India. A 2026 review names variable access to simple, accurate and affordable testing as the overarching equity gap (Shook 2026).

In the Multicenter Study of Hydroxyurea (MSH), a double-blind randomized trial in 299 adults with three or more painful crises a year, those given hydroxyurea had a median of 2.5 crises a year versus 4.5 with placebo, fewer had acute chest syndrome (25 vs. 51), and fewer needed transfusions (48 vs. 73); the trial was stopped after a mean follow-up of 21 months. The rationale was that hydroxyurea raises fetal hemoglobin, which inhibits sickling (Charache 1995). The FDA approved hydroxyurea for adults with sickle cell disease in 1998 and for children in 2017 (Egesa 2022).

When the FDA approved L-glutamine in July 2017, it described it as the first treatment approved for sickle cell disease in almost 20 years, with only one other drug approved before it (FDA, July 7, 2017). Two more drugs followed in 2019: voxelotor, an HbS polymerization inhibitor, given accelerated approval for patients 12 years and older and extended in 2021 to ages 4 to 11 (FDA, September 26, 2024), and crizanlizumab, an antibody against the adhesion molecule P-selectin (Ikolo 2026), approved in November 2019 (FDA label, 11/2019). On September 26, 2024 the FDA announced that the manufacturer was voluntarily withdrawing voxelotor from the market: in postmarketing trials patients given voxelotor had a higher rate of vaso-occlusive crises and more deaths than those given placebo, two real-world registry studies also showed a higher crisis rate, and the manufacturer concluded that its benefit does not outweigh its risk (FDA, September 26, 2024). Before the gene therapies, stem-cell transplantation was the only curative intervention (Egesa 2022).

On December 8, 2023 the FDA approved the first two cell-based gene therapies for sickle cell disease, both for patients 12 years and older. Exagamglogene autotemcel (exa-cel), approved for patients with recurrent vaso-occlusive crises, is the first FDA-approved therapy to use CRISPR/Cas9 genome editing: the patient's blood stem cells are edited so that, once transplanted back, they increase production of fetal hemoglobin, which prevents sickling. Lovotibeglogene autotemcel (lovo-cel), approved for patients with a history of vaso-occlusive events, uses a lentiviral vector to modify the stem cells so that they produce HbA^T87Q, a gene-therapy-derived hemoglobin that functions similarly to normal adult hemoglobin. Both are made from the patient's own blood stem cells and are given once, as part of a stem cell transplant, after myeloablative conditioning (high-dose chemotherapy) (FDA, December 8, 2023). On July 1, 2026 the FDA extended the exagamglogene indication to patients aged 2 to under 12 years, for both sickle cell disease with recurrent vaso-occlusive crises and transfusion-dependent thalassemia (FDA approval letter, July 1, 2026); its current label covers patients aged 2 years and older and states that it has not been studied in clinical trials in patients younger than 5 (FDA label, exagamglogene autotemcel, 07/2026). The lovotibeglogene indication remains patients 12 years of age or older (FDA label, lovotibeglogene autotemcel).

More than a century after Herrick described Noel's sickled cells, medicine had moved from the abnormal molecule (1949) and the single amino acid (1956–1957) to genetically modifying a patient's own blood stem cells. A 2020 retrospective notes that curative treatments such as stem-cell transplantation and gene therapy are expensive and require advanced medical facilities, and are therefore not available to the vast majority of the world's patients (Eaton 2020).

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Key Research Papers

The references below are the primary historical papers (the 1910 Herrick and 1922 Mason papers are indexed in PubMed only through later reprints, which are labeled as such), followed by the histories, reviews and trials cited in the text. PubMed topic searches follow at the end.

1. Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. Archives of Internal Medicine. 1910;6(5):517-521. — doi:10.1001/archinte.1910.00050330050003
2. Pauling L, Itano HA, Singer SJ, Wells IC. Sickle cell anemia, a molecular disease. Science. 1949;110(2865):543-548. — doi:10.1126/science.110.2865.543
3. Ingram VM. A specific chemical difference between the globins of normal human and sickle-cell anaemia haemoglobin. Nature. 1956;178(4537):792-794. — doi:10.1038/178792a0
4. Ingram VM. Gene mutations in human haemoglobin: the chemical difference between normal and sickle cell haemoglobin. Nature. 1957;180(4581):326-328. — doi:10.1038/180326a0
5. Allison AC. Protection afforded by sickle-cell trait against subtertian malarial infection. British Medical Journal. 1954;1(4857):290-294. — doi:10.1136/bmj.1.4857.290
6. Neel JV. The inheritance of sickle cell anemia. Science. 1949;110(2846):64-66. — doi:10.1126/science.110.2846.64
7. Savitt TL, Goldberg MF (1989). Herrick's 1910 case report of sickle cell anemia: the rest of the story. JAMA. 1989;261(2):266-271. (A 1989 historical study of the 1910 case, not the 1910 paper itself.) — PubMed PMID: 2642320
8. Serjeant GR. The natural history of sickle cell disease. Cold Spring Harbor Perspectives in Medicine. 2013;3(10):a011783. — doi:10.1101/cshperspect.a011783
9. Steensma DP, Kyle RA, Shampo MA. Walter Clement Noel—first patient described with sickle cell disease. Mayo Clinic Proceedings. 2010;85(10):e74-e75. — PMC: PMC2947974 — PubMed PMID: 20931692
10. Mason VR (1922). Sickle cell anemia. JAMA. 1922;79:1318 (published 14 October 1922). — doi:10.1001/jama.1922.02640160038012
11. Mason VR (1985). Landmark article Oct. 14, 1922: Sickle cell anemia. By V.R. Mason. JAMA. 1985;254(14):1955-1957. (JAMA's 1985 reprint of the 1922 article; this reprint, not the 1922 original, is the PubMed record.) — PubMed PMID: 3900438
12. Ikolo B, Oyelami M, Mgbeke O, Jones K, Thomas S, Ikolo F. Sickle cell disease: from ancient origins to modern breakthroughs in gene therapy. Biomedicines. 2026;14(7):1649. — PubMed PMID: 42512120
13. Herrick JB (2001). Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. 1910. Yale Journal of Biology and Medicine. 2001;74(3):179-184. (Reprint of the 1910 paper in the journal's “Classics of Biology and Medicine” series.) — PubMed PMID: 11501714
14. Ingram VM. Abnormal human haemoglobins. I. The comparison of normal human and sickle-cell haemoglobins by fingerprinting. Biochimica et Biophysica Acta. 1958;28(3):539-545. — PubMed PMID: 13560404
15. Eaton WA. Hemoglobin S polymerization and sickle cell disease: a retrospective on the occasion of the 70th anniversary of Pauling's Science paper. American Journal of Hematology. 2020;95(2):205-211. — PubMed PMID: 31763707
16. Gormley M. The first ‘molecular disease’: a story of Linus Pauling, the intellectual patron. Endeavour. 2007;31(2):71-77. — PubMed PMID: 17602747
17. Dorneles J, de Menezes Mayer A, Chies JAB. Sickle cell anemia and inflammation: a review of stones and landmarks paving the road in the last 25 years. Hematology Reports. 2025;17(1):2. — PubMed PMID: 39846606
18. Allison AC. The distribution of the sickle-cell trait in East Africa and elsewhere, and its apparent relationship to the incidence of subtertian malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene. 1954;48(4):312-318. — PubMed PMID: 13187561
19. Allison AC. Genetic control of resistance to human malaria. Current Opinion in Immunology. 2009;21(5):499-505. — PubMed PMID: 19442502
20. Kariuki SN, Williams TN. Human genetics and malaria resistance. Human Genetics. 2020;139(6-7):801-811. — PubMed PMID: 32130487
21. Starlard-Davenport A. Complexity within simplicity: exploring the multifactorial nature of sickle cell disease. American Journal of Human Genetics. 2025;112(7):1499-1503. — PubMed PMID: 40482641
22. Jacobs-McFarlane CT, Liu A. Sickle cell disease: treatment options of the past, present, and future. American Journal of Nursing. 2026;126(1):26-33. — PubMed PMID: 41437446
23. Nzewi E. Malevolent ogbanje: recurrent reincarnation or sickle cell disease? Social Science & Medicine. 2001;52(9):1403-1416. — PubMed PMID: 11286364
24. Munung NS, Treadwell M, Kamga KK, et al. Caught between pity, explicit bias, and discrimination: a qualitative study on the impact of stigma on the quality of life of persons living with sickle cell disease in three African countries. Quality of Life Research. 2024;33(2):423-432. — PubMed PMID: 37889387
25. Egesa WI, Nakalema G, Waibi WM, et al. Sickle cell disease in children and adolescents: a review of the historical, clinical, and public health perspective of sub-Saharan Africa and beyond. International Journal of Pediatrics. 2022;2022:3885979. — PubMed PMID: 36254264
26. Konotey-Ahulu FI. Clinical genetics: Ghanaian gratitude for British and Hungarian contributions: a personalized historical perspective. Ghana Medical Journal. 2009;43(4):175-178. — PubMed PMID: 21326998
27. Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial. New England Journal of Medicine. 1986;314(25):1593-1599. — PubMed PMID: 3086721
28. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia (Multicenter Study of Hydroxyurea). New England Journal of Medicine. 1995;332(20):1317-1322. — PubMed PMID: 7715639
29. Shook LM, Ware RE. Advances and gaps in global newborn screening for sickle cell disease. International Journal of Neonatal Screening. 2026;12(1):4. — PubMed PMID: 41718418

PubMed Topic Searches

1. Konotey-Ahulu FI — sickle cell disease in Ghana. — Search PubMed
2. Sickle cell disease in African traditional medicine and indigenous knowledge. — Search PubMed
3. History of hydroxyurea and the Multicenter Study of Hydroxyurea (MSH). — PubMed: hydroxyurea sickle cell — MSH and history

External Authoritative Resources

1. National Human Genome Research Institute (NHGRI) — Sickle Cell Disease
2. NHLBI (National Heart, Lung, and Blood Institute) — Sickle Cell Disease
3. U.S. FDA — First Gene Therapies Approved for Sickle Cell Disease (December 8, 2023)
4. U.S. FDA — Exagamglogene autotemcel supplement approval letter, ages 2 to under 12 (July 1, 2026)
5. U.S. FDA — Exagamglogene autotemcel prescribing information (07/2026)
6. U.S. FDA — Lovotibeglogene autotemcel prescribing information (12/2023)
7. U.S. FDA — Voluntary market withdrawal of voxelotor (September 26, 2024)
8. U.S. FDA — Approval of L-glutamine for sickle cell disease (July 7, 2017)
9. U.S. FDA — Crizanlizumab prescribing information (11/2019)

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Connections

• Hematology
• Sickle Cell Disease (overview)
• Anemia
• Thalassemia
• Malaria
• All Conditions

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