Sickle Cell Anemia, a Molecular Disease. WITH: A Specific Chemical Difference Between the Globins of Normal Human and Sickle-Cell Anæmia Hæmoglobin

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FIRST EDITIONS, OFFPRINT ISSUES, IN ORIGINAL WRAPPERS, OF PAPERS ANNOUNCING THE DISCOVERY OF THE MOLECULAR BASIS OF SICKLE-CELL ANEMIA. Determining the extent to which biological traits (including susceptibility to certain diseases) are linked to genetic factors presents difficult, often intractable, analytical problems. Multiple genetic factors may interact in complex ways with each other and with environmental factors in shaping a single characteristic or trait of an organism; conversely, a single genetic change can have cascading effects on a broad range of traits. In some cases, however, specific genetic abnormalities can be linked in a clean, direct, and simple manner to specific diseases. An example of this is provided by the research described in the papers offered here, which firmly established the genetic and biological underpinning of sickle-cell anemia. Biologist Graham C. Walker called this work "one of the absolutely seminal discoveries in the history of molecular biology." (New York Times, August 25, 2006 obituary of Vernon Ingram). "[Approximately 10%] of African-Americans and as many of 25% of black Africans carry a single copy of . the gene for sickle-cell hemoglobin (hemoglobin S). Individuals who carry two copies of . the gene for hemoglobin S suffer from sickle-cell anemia, in which [the unoxygenated form of hemoglobin S] forms insoluble filaments that deform erythrocytes [i.e., red blood cells, into a distinctive sickle shape]. . In this painful, debilitating, and often fatal disease, the rigid-sickle-shaped [red blood] cells cannot easily pass through the capillaries. Consequently, in a sickle-cell 'crisis,' the blood flow to some tissues may be completely blocked, resulting in tissue death." (Donald Voet, et al., Fundamentals of Biochemistry: Life at the Molecular Level, 5th ed. 2016). Molecules of hemoglobin, like those of all proteins, consist of chains of amino acids, with each amino acid in the chain connected to the next by a linkage known as a peptide bond. (The hemoglobin molecule is actually made up of four such chains.) In sickle-cell anemia, one amino acid (glutamic acid) is substituted for a different amino acid (valine) at a particular position in at least one of those four chains. That change in a single amino acid (out of roughly 560) is sufficient to create a "sticky" patch on the exterior surface of the molecule that can interact with a similar patch on a neighboring hemoglobin molecule, leading to the formation of the insoluble molecular aggregates that cause the condition. The amino-acid substitution is in turn caused by a change (as a result of an inherited mutation) in a single base pair in the hemoglobin gene. "The nature of the disease was first understood by Linus Pauling, with what was even for him an astounding flash of physical intuition": that sickle-cell anemia "must be a molecular disease - a disease of the hemoglobin molecule." In 1949 Pauling and his student Harvey Itano established through electrophoresis (separation of molecules based on their electric charge) that molecules of sickle-cell hemoglobin had two to four more net positive charges than normal hemoglobin. (First offered paper.) "In July of that year, James V. Neel, a specialist in human genetics at the University of Michigan, published a crisp, short paper proving from the incidence of sickle-cell disease and the trait in American Negro families that the cause was a mutant gene, inherited in a Mendelian manner." The work of Pauling, Itano, and Neel thus provided "the first clear case of a change produced in a protein molecule by an allelic change [that is, a change in one of a homologous pair] in a single gene involved in synthesis." (Quotations from Horace F. Judson, The Eighth Day of Creation [expanded edition 1996]). "Pauling's article was extremely important for the history of modern medicine: by showing how a molecular disorder can explain the symptoms of an illness, it founded molecular medicine." (Michel. N° de ref. del artículo 2265

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Título: Sickle Cell Anemia, a Molecular Disease. ...
Editorial: American Association for the Advancement of Science, Washington, DC
Año de publicación: 1949
Encuadernación: Original Wrappers
Condición: Fine
Edición: First edition.