The origin of molecular medicine


The data in the Figure above changed the face of medical research.
It showed for the first time that disease can have a molecular basis.
It was another great scientific achievement and bold discovery of Linus Pauling.

The Figure is discussed in chapter 8 of Nelson's Biological Physics: Energy, Information, Life. He states:
In a historic discovery, Linus Pauling and coauthors showed in 1949 that the red blood cells of sickle-cell patients contained a defective form of hemoglobin. Today we know that the defect lies in parts of hemoglobin called the β-globin chains, which differ from normal β-globin by the substitution of a single amino acid, from glutamic acid to valine in position six. This tiny change (β-globin has 146 amino acids in all) is enough to create a sticky (hydrophobic) patch on the molecular surface. The mutant molecules clump together, forming a solid fiber of fourteen interwound helical strands inside the red cell and giving it the sickle shape for which the disease is named. The deformed red cells in turn get stuck in capillaries, then damaged, and destroyed by the body, with the net effect of creating pain and anemia.
In 1949, the sequence of β-globin was unknown. Nevertheless, Pauling and coauthors pinpointed the source of the disease in a single molecule. They reasoned that a slight chemical modification to hemoglobin could make a correspondingly small change in its titration curve, if the differing amino acids had different dissociation constants. 
A nice article  about the history is by William Eaton.

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