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First molecular explanation of disease

Hemoglobin has played a central role in the understanding of many biochemical and biophysical principles, as Eaton and colleagues point out on page 351 of this issue of Nature Structural Biology. However, the role of hemoglobin in the understanding of genetic disease has been equally powerful. Over 300 abnormal hemoglobins — such as sickle cell hemoglobin — have been discovered, most of which are either neutral or harmful to their carriers, and numerous thalassemias, which result from defective synthesis of one or more hemoglobin chains, have been identified. Notably, sickle cell anemia was the first genetic disease to be examined at the molecular level.

The first documented case of sickle cell anemia was published in 1910 by a physician named James Herrick. He described a 20 year old college student who was severely anemic. A smear of this patient's blood showed that "the shape of the red cells was very irregular, but what especially attracted attention was the large number of thin, elongated, sickle-shaped and crescent-shaped forms"1. Complicating a diagnosis were additional problems: cardiac enlargement, jaundice, possible kidney damage, and swelling of the lymph nodes. Nevertheless, Herrick suggested that some "change in the composition of the [red blood] corpuscle itself may be the determining factor" in the manifestation of these conditions.

During the 1940's, evidence for the hereditary nature of sickle cell anemia developed and in 1949, this disease caught the attention of Linus Pauling. Since red blood cells contain large amounts of hemoglobin, Pauling thought it would be worthwhile to examine the properties of hemoglobin obtained from sickle cells. He and his colleagues were not disappointed: they found that both the oxygenated and deoxygenated forms of sickle cell hemoglobin had higher isoelectric points (7.09 and 6.91, respectively) than those of hemoglobin from normal erythrocytes (6.87 and 6.68, respectively), suggesting that sickle cell hemoglobin is more positively charged than normal hemoglobin. Pauling and colleagues published their results in a paper entitled "Sickle cell anemia: a molecular disease", as it was the first demonstration of "a change produced in a protein molecule by an allelic change in a single gene"2.

In 1957, Vernon Ingram reported the exact difference between sickle cell and wild type hemoglobin. His experiments showed that not all of the tryptic peptides from sickle cell and normal hemoglobin had matching positions when run out on an electrophoresis/chromatography two dimensional gel: one pair of peptides ran differently. Ingram sequenced these two peptides and showed that the β chain of sickle cell hemoglobin had a valine residue at a position where normal hemoglobin had a glutamic acid residue3. The atomic structure of hemoglobin, determined by Max Perutz and colleagues4, showed that this residue position is located on the surface of the protein. The mutation makes sickle cell hemoglobin less soluble and more prone to form the distinct fibrous precipitates that cause the erythrocytes to adopt the deformed 'sickle' shape. The sickle cells can become trapped in small blood vessels, resulting in organ damage, and they rupture more easily, leading to anemia. Today, despite the detailed molecular explanation of the cause, sickle cell anemia is still a serious clinical problem.


  1. Herrick, J.B. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. Arch. Intern. Med. 6, 517– 521 (1910).

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  2. Pauling, L., Itano, H.A., Singer, S.J. & Wells, I.C. Sickle cell anemia: a molecular disease. Science 110 , 543–548 (1949).

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  3. Ingram, V.M. Gene mutation in human haemoglobin: the chemical difference between normal and sickle cell haemoglobin. Nature 180, 326–328 (1957).

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  4. Perutz, M.F., Bolton, W., Diamond, R., Muirhead, H. & Watson, H. Structure of haemoglobin. An X-ray examination of reduced horse haemoglobin. Nature 203, 687– 690 (1964).

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Smith, T. First molecular explanation of disease. Nat Struct Mol Biol 6, 307 (1999).

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