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How did Linus Pauling connect sickle-cell anemia to an altered protein?

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Diagram showing how epinephrine binding to a beta-adrenergic receptor on a cell membrane activates a G-protein, which then stimulates adenylyl cyclase to convert ATP into cyclic AMP (cAMP), leading to physiological effects such as increased heart rate, blood vessel dilation, and glycogen breakdown. — Biochemistry In biochemistry, researchers study the chemical substances and processes that occur in living organisms and cells. In particular, various processes by which cells gain energy, such as epinephrine-stimulated cAMP synthesis, have been deduced through the study of biochemistry.

In 1949, American chemist Linus Pauling and his colleagues identified sickle-cell anemia as the first "molecular disease" by demonstrating that it is caused by a structural alteration in a protein.12

Pauling hypothesized that the characteristic sickling of red blood cells observed in the disease might stem from a genetic mutation affecting the globin portion of hemoglobin. To test this, his team compared hemoglobin extracted from the red blood cells of healthy individuals with hemoglobin taken from patients with sickle-cell anemia. They discovered that the two forms of the protein behaved differently, providing clear evidence that the disease was caused by a mutant gene directing the formation of an abnormal, structurally altered protein. This discovery was a landmark moment in biochemistry, as it established that inherited metabolic diseases could result from specific defects in protein structure.21