28 JOHN H. NORTHROP 



A number of reports of the formation of antibodies in vitro have 

 been made (Ostromuislenskii, 1916; PauHng, 1940) but the identity 

 of the substance prepared in this way with the natural antibody has not 

 been estabhshed. It must be remembered in connection with these experi- 

 ments that owing to experimental difficulties whole blood cannot be 

 used in vitro. Failure of the experiment when carried out with serum, 

 plasma, defibrinated blood, or in the presence of anti-coagulants, there- 

 fore, does not prove that the reaction cannot occur in the circulation. 



Burnet's Hypothesis. Burnet, Freeman, Jackson, and Lush (1941) 

 consider the formation of antibodies to be analogous to the formation 

 of adaptive enzymes. Indeed, there are many points of similarity. Anti- 

 bodies and enzymes may both be divided into two general classes- 

 normal or physiological, and acquired or adaptive. The "normal" en- 

 zymes or antibodies are present in all individuals of the species and are 

 inherited (cf. Landsteiner, 1945, p. 132). The ability to form adaptive 

 enzymes also appears to be inherited (Lindegren, Spiegelman, and 

 Lindegren, 1944). "Acquired" antibodies or adaptive enzymes are 

 formed in response to the presence of a foreign substance, and their 

 formation stops sooner or later after removal of this substance. 



Both antibodies and adaptive enzymes have a specific relation to the 

 substance which caused their formation. In some cases adaptive enzyme 

 reactions are more specific than the antibody reactions (Dubos, 1939)- 

 The reaction of enzymes with substances formed during the reaction 

 is quantitatively similar to the reaction between antigen and antibody 

 (Northrop, 1922; and Zinsser, 1923). The antigen-antibody complex 

 is less dissociated than most enzyme-product compounds. 



According to Burnet, normal globulin is synthesized by a special 

 proteinase. Injection of antigen results in a reaction between this pro- 

 teinase and the antigen, which destroys the antigen and modifies the 

 proteinase. This modified proteinase causes the formation of antibody 

 instead of normal globulins, and also causes replicas of itself to be 

 formed. The modified proteinase resulting from reaction with the anti- 

 gen decreases gradually when antigen is no longer present, as do adap- 

 tive enzymes. 



The qualitative and quantitative differences in antibody formation are 

 therefore accounted for. The hypothesis also accounts for the fact that 

 small quantities of antigens can cause the production of very large 

 quantities of antibody and predicts that antibody formation may con- 

 tinue for an indefinite length of time after the antigen and even its 

 decomposition products have disappeared. 



