INITIAL RADIATION DAMAGE AT SUB-CELLULAR LEVEL 17 



In a certain way our theory is so obvious that it appears to us as a 

 "lapalissade"t. 



The cell is a network of phospholipid membranes and one of their 

 chief functions is to keep certain substrates and enzymes apart. If 

 these barriers are disrupted, either by forming holes or altering their 

 selective permeability in some way, serious biochemical disturbances 

 will result. 



The release of degradative enzymes, for example, could give rise to 

 damage to nucleic acids and proteins. But this is only one of the possible 

 mechanisms by which an interference with internal cell structures could 

 lead to cellular lesions, and reactions such as coagulation of nucleo- 

 protein by calcium ions may have to be considered. Possibly the actual 

 l)iochemical process that is initiated by membrane damage may vary 

 for different cells and for different types of lesions. 



To break down fine intracellular structures, several ionizations 

 acting in conjunction may be necessary and this could explain the 

 superiority of densely ionizing over sparsely ionizing radiations in 

 initiating cellular lesions (i.e. a given amount of explosive is much more 

 effective in knocking down a wall in the form of one cannon shell than 

 in the form of many rifle bullets none of which can penetrate). 



A mechanism by which oxygen enhances the radiation lesions of 

 sparsely ionizing radiations can be envisaged for membrane damage. 

 The phospholipid membrane may undergo a chain reaction with oxygen 

 which is initiated by an ionization for they contain unsaturated fats 

 and in this way the effect of a single ionization may be greatly multi- 

 plied. With densely ionizing radiations this multiplication effect may 

 not be necessary as the damage produced by several ionizations close 

 together is already sufficient. 



The possibility that damage to membranes contributes to the killing 

 of lymphocytes by radiation is indicated by electron microscopic studies. 

 Four hours after 1,000 rads are given to the thymus of rats all the 

 cells and, in particular, the nuclei show gross morphological abnormali- 

 ties (i.e. pyknosis) when fixed with heavy-metal-containing fixatives 

 and then stained by the methods developed by Trowell (1952). Yet 

 when these same cells are examined in the electron microscope (with 

 osmium fixation), the shape of the nucleus is quite unaltered and no 

 morphological abnormalities can be seen (Alexander, 1961). The heavy 

 metal fixative used to show up pyknosis causes clumping of isolated 

 nucleoprotein whether this has been irradiated or not. We believe that 



t The early release of enzymes may be the reason for the iDrimary step of their inaetiva- 

 tion which may be observed several hours or days after irradiation. Enzj-mes when 

 linked to mitociiondria or microsomes are inactive but protected against destruction; 

 when liberated, they may become a substrate for proteases similarly released. 



