MUTATIONS AND MOLECULAR DISEASES 157 



vidual, of antibodies (big molecules?) which are specific to that individual, 

 and incompatible with those built by any other individual for the same pur- 

 pose, is a well known phenomenon. Thus each individual has a specific bio- 

 chemistry and a biophysics of his own, which becomes manifested in many 

 ways. It is not surprising, then, that even small changes in structure or 

 composition of certain large molecules can sometimes have disastrous 

 results. 



A few examples will illustrate the point. No attempt is made to be ex- 

 haustive. Lathe's thesis 1 reviews several other molecular diseases. 



Molecular Diseases 



There is both a broad, generic connotation and a rather restricted, spe- 

 cialized one associated with the term "molecular diseases. " In the sense 

 that all diseases involve molecules which are incompatible with the chem- 

 istry or the physics of the system, all diseases are "molecular. " However, 

 in the more restricted sense, the term has evolved to mean diseases caused 

 by apparently small modifications of the chemical composition or the physi- 

 cal structure of a particular molecule. The hemoglobin diseases, recognized 

 only within the last decade, are now the classic example. 



Hemoglobins : There are at least ten known modifications of the hemo- 

 globin molecule, each of which is associated with a pathologic condition. 

 The normal molecule is characterized by certain values for sedimentation 

 and diffusion constant (thence molecular wt.), electrophoretic mobility, elec- 

 tric charge as a function of pH (determined by titration), solubility, ultra- 

 violet absorption spectrum, etc. The most celebrated variant, S, which is 

 found in erythrocytes from people with sickle-cell anemia, differs from the 

 normal, A, principally in the manner in which it moves under the influence 

 of an electric field: it moves faster, and at pH = 7, toward the cathode, 

 whereas .4 is negatively charged at pH = 7 and moves toward the anode. 



Some of the pertinent characteristics of ten different forms of the hemo- 

 globin molecule have been collected in Table 6-5. Although the differences 

 were first observed clinically, and then correlated with differences in physi- 

 cal properties, recent work has established that the differences arise because 

 of different composition or arrangement in the amino-acid sequences of the 

 protein. There are about 600 amino acids in the molecule. X-ray diffraction 

 studies have shown that type A (normal adult human hemoglobin) mole- 

 cules consist of four intertwined polypeptide chains. Two of these have a 

 valine, then a leucine residue just prior to attachment to the nitrogen of the 

 porphyrin (heme) group; two others have a valine, histidine, leucine sequence 

 before attachment to the (iron-containing) porphyrin group. It is now 

 known that modifications occur right at that point: a different sequence, or 

 even different amino acids in the sequence, can occur. 



