GENETICS OF INFECTIOUS DISEASES 401 



Webster's selection experiments. With this great wealth of materials he initiated the 

 intensive investigations that are still in progress. 



The type of selection experiment used to produce resistant and susceptible lines 

 of mice bears comment. Parenthetically, a number of strains have been produced by 

 inbreeding without selection, much as the cancer strains have been developed. Pro- 

 ponents of selection theory choose their characters for ease of measurement, and this 

 introduces elements of artificiality. Even selection for DDT resistance falls in a special 

 category, because the host is subjected to an artificial insult unlike anything it has faced 

 during its long evolutionary history. Selection for resistance to infection, on the other 

 hand, duplicates many of the features encountered in naturally occurring epizootics. 

 The disease produced by intraperitoneal inoculation with known numbers of organisms 

 of murine typhoid is identical in all its essential features to the disease as it occurs in 

 an epizootic, because in mice the acute form of the disease is a septicemia and not 

 primarily a gastrointestinal infection. 



As in work with malignant neoplasms, inbred lines provide the investigator with 

 a tool of inestimable value for examining the nature of the syndrome, but there are 

 certain pitfalls in a study of the mechanisms of genetic resistance. To look for strain 

 differences is an important part of the methodology, but the number of degrees of 

 freedom available for correlation studies depends on the number of inbred strains 

 and is independent of the numbers of mice. Furthermore, the degrees of freedom 

 may be depleted in the search for clues. It is noteworthy that Dr. Gowen has not 

 been content merely to isolate mechanisms of resistance, but he has attempted to estab- 

 lish physiologic relationships and to apply a variety of techniques. It should also be 

 emphasized that he and his associates have taken elaborate precautions to separate 

 the role of natural resistance from that of acquired immunity, to control dosage, and 

 to apply genetic techniques of crossbreeding. 



The nature of some components of natural resistance should be commented on 

 briefly. Gowen and Calhoun 466 found that level of resistance and total leucocyte 

 count were related. Subsequent studies using X irradiation have added strength to 

 the conclusion that high leucocyte count and a high level of resistance are causally 

 related. This stimulated some work of my own. I started with what now seems to 

 have been a naive assumption, namely that resistance could be synthesized by selecting 

 for single components. I selected for total leucocyte count and obtained a high line 

 with total count of more than 1 5,000 cells per mm 3 and a low line with less than 5,000 

 cells per mm 3 . The outbred line has a mean count of 9,000 cells per mm 3 . When 

 mice were inoculated with standard doses of several strains of S. typhimurium, there were 

 significant and consistent differences between strains in mortality and days to death. 

 But the resistance levels were opposite to expectation on the assumption that the charac- 

 ter selected is an additive component of resistance. 1377 Selection for blood pH gave 

 similar results. 1377 Hill et.al. 577 also obtained similar results in that mice selected for 

 resistance to a partially purified, toxic fraction isolated from S. typhimurium proved more 

 susceptible than the controls when they administered live organisms either per os or 



