the immune response; to study the composition, structure, and 

 function of normal and cancer cell membranes; and to define the role 

 of membrane antigens in tumor development and rejection. 



The various and diverse Approaches outlined in the Plan share a 

 common and important characteristic: the basic role of fundamental 

 understanding of biological processes in attaining the Goal of the 

 Program. Success is conditioned entirely upon gaining sufficient 

 understanding of the normal life of a tissue cell, and the manner in 

 which it is altered after the neoplastic transformation. 



One of the largest gaps in modern biology is detailed knowledge 

 about the mechanism of normal cell differentiation and the means by 

 which such cells maintain their stability throughout life. The question 

 of how normal cells acquire and maintain their differentiated 

 character encompasses some of the most important unknowns in cell 

 biology. The answer to this question — which will require much 

 fundamental research — is essential to a successful attack on cancer. 



Although clues abound, there is as yet no satisfactory description 

 of the fundamental nature of the neoplastic transformation involved 

 in cancer. Indeed, present knowledge is insufficient to assure that the 

 structure or function which is altered in the course of that 

 transformation has been properly described. Even if this critical 

 information were available, a large effort would still be required to 

 achieve the major Program Objectives, for success will require 

 answers to most of the other questions posed. 



If human cancers are caused by viruses — whether they invade 

 from without or are carried in the genome from birth — it is not clear 

 what those viruses actually do that results in malignancy. To repeat, it 

 is difficult to understand how malignant cells escape from an 

 otherwise normal organ, when understanding is lacking of what 

 prevents normal cells from doing so. Plainly, since cancerous cells 

 differentiate and undergo repeated divisions, they escape from some 

 control mechanism. But the nature of the control mechanisms 

 operative in the normal cell itself is totally unknown. 



On the surface of cancer cells are macromolecules, known only by 

 their immunological properties, which are not present on the surface 

 of the normal cells from which the cancer cells developed. But the 

 relationship, if any, between the presence of these macromolecules 

 and the uncontrolled growth and diffusion of cancer cells is unknown 

 at present. Whether the macromolecules (which are called "tumor 

 antigens") are a primary aspect of neoplasia, or a secondary 

 consequence, remains to be established. Their presence, however, 

 furnishes another possible clue. It may be that the neoplastic 

 transformation is not a rare event which inevitably leads to cancer but 

 rather a frequent process which relatively rarely culminates in the 

 disease. This could be the case if such transformed cells are usually 



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