548 THE BACTERIOPHAGE 



mechanism of this stimulation still remains unknown. As a result, the activity of 

 intracellular ferments is increased, and the rate of multiplication is exaggerated.' 

 Some of the products escape from the cells^ into the medium, and in turn produce a 

 stimulating effect on newly formed cells. ^ These products represent the active agent 

 (bacteriophage). They are toxic only to closely related species of bacteria, hence the 

 multiplicity and relative specificity of different bacteriophages. ^ The second stage of 

 the process may or may not follow the first, depending on circumstances. It consists 

 in the swelling and eventual bursting of cells due to the intake of water following the 

 increase in osmotic pressure within the cells. Any change in environment which will 

 tend to interfere with the progress of intracellular digestion or with the freedom of 

 passage of water from the medium into the cells may prevent the swelling and dis- 

 appearance of bacteria. 



THE NATURE OF RESISTANCE TO PHAGE ^ 



One of the most interesting and yet comparatively little-understood phenomena 

 connected with the lysis of bacteria by phage is the development of resistant cultures, 

 which takes place in vivo as well as in vitro.^ WTien susceptible bacteria are grown in 

 broth in the presence of bacteriophage, multiplication of bacteria is at first noticeably 

 accelerated,* but later they undergo more or less rapid lysis, and the initial turbidity 

 of the culture disappears. In exceptional cases the culture may be completely and 

 permanently cleared and rendered sterile. In the majority of cases, however, a cer- 



• Somewhat similar changes were postulated recently by Armstrong (Armstrong, H. E.: ibid., 

 8, 653. 1925-27) in the case of excitation of plant cells. 



^ Some of the experiments on artificial fertilization of eggs suggest that the agents which in- 

 crease the activity of a cell may cause also an increase in the permeability of the cell membrane, thus 

 permitting the escape of some of the intracellular constituents into the medium (Lyon, E. P., and 

 Shackell, L. P.: Science [N.S.] 32, 249. 1910). 



^ It has been recognized for a long time that metabolic products of bacteria are toxic for homol- 

 ogous or closely related species of bacteria (Eijkman, C: Centralbl. f. BaktcrioL, Orig., 37, 436. 

 1904; von Liebermann, L.: Klin Wchnschr., 2, 1240. 1923). More recently, Osterhout (Osterhout, 

 W. J. v.: J . General Physiol., 7, 561. 1925) has shown that also unchanged intracellular contents 

 may be highly toxic when applied to homologous cells from without. These effects, as ordinarily ob- 

 served, are depressing in character, whereas in the case of bacteriophage, the effect is that of stimula- 

 tion. This difference in effect may be due to the difference in the nature of substances concerned, but 

 it is conceivable that it may simply depend on the concentration of injurious agent (Bronfcnbrenncr, 

 J.: Proc. Soc. E.xper. Biol, of Med., 12, 136. 1915; ibid., 18, 94. 1920). 



"The attention of the writer has been called recently to a very interesting paper (Sanfclicc, V.: 

 Zlschr.f. Hyg. u. Injektionskrankh., 76, 257. 1914), which explained in 1914 the mechanism of trans- 

 missibility of epithelioma contagiosiim of pigeons on an essentially similar basis. Sanfelice was able 

 to extract from the involved areas of the skin a nucleoprotein-like substance which was regenerated 

 anew when injected into the epithelial cells of the skin of normal birds, and perpetuated the disease 

 in series as if it were a living virus. 



sDimtza, A.: Centralbl. f. BaktcrioL, Orig., loi, 171. 1927; Sonnenschein, C: ibid., 97, Bei- 

 heft, 312. 1926; Kauffmann, F.: Ztschr. f. Hyg. u. Injcklionskrankh., io6, 520. 1926; Grumbach, A., 

 and Dimtza, A.: Ztschr. f. Immunitdlsjorsch. u. e.vper. Therap., 51, 176. 1927. 



^Doerr, R., and Gruninger, W.: loc. cit.; Schwarzman, G.: loc. oil.; Saldanha, A.: loc. cit.; 

 Hadlcy, P.: loc. cit.; Doerr, R., and Gruninger, W.: Sclncciz. mcd. Wchnschr., 52, 761. 1922. 



