3168 Commentary: Lederberg Proc. Nrrtl. Acad. Sci. USA 93 (1996) What are the most likely targets for the application of phage therapy? We think, first of all. of organisms recalcitrant to the usual antibiotics or species in which high-level resistance has emerged (13) and is being promiscuously disseminated by plasmid vectors. Here some pseudomonads and other oppor- tunistic invaders are notorious. Then there are settings in which individual therapy may be less than feasible. or too costly. If the transmission of cholera or dysentery could but be mitigated, the refugee camps bordering Rwanda might be less terrifying. Yes. d'Herelle had enunciated these dreams (15). and today we are somewhat put off by the anecdotal quality of the evidence that he assembled. Even so. it is ambitious but not preposterous to suggest that newer knowledge might yet engen- der some workable weapons for the medical armamentarium. R/loving from pestilence to famine, a more likely arena for early application is in agriculture, to deal with bacterial infestations like citrus canker (Xarzthomonas citri) and Erwinia fire blight. There have already been suggestions that the synecology of bacteriophage and bacterial pathogens may account for fluctuations in their outbreaks (16. 17). Genetic engineering has been applied to the refinement of entomopha- gous viruses (IX) and of bacteria to produce insect toxins (19) hut not yet to bacteriophage control. An almost unknown terrain is occupied by fungal pests. which have the potential to wipe out a year's crop of potato, maize, or wheat, and have done so with historic consequences. Virus-like agents are known in many fungi (20). but they are not (or are not readily) now transmitted by horizontal exogenous cross-infection (21): there would be a worthy challenge to contemporary biotechnology. Hopefully that would also be accompanied by the most prudent inquiry about what might go wrong, but the long-term prospects of earth's food supply are not so robust that we can afford to ignore such opportumties. I. SW ift. J. ( 1942) in A IVW Dictionwy of Quota&m on Historical Prit~cipkr fkm Ancient awl ~Lfodern Sources, ed. Mencken, H. L. (Knopf, Newt York), p. 1712. 2. Duckworth. D. H. (1976) Bacterial. Rev. 40, 793-802. 3. Bloom, H. ed. ( 1988) SinclairLeu~is'.vArrowsmitl~. Modern Critical frztq~retatiorts (Chelsea House, New York). 4. Sullivan. D. J. (1987) AII~U. Rev. Enfomol. 32, 49970. r 3 Waksman, S. A. (1954) in !vy Life with the Microbes, (Simon & Schuster. Nevv York). p. 364. 6. Wilson, G. S. & Miles, A. A., eds. (1955) Toplq & Wilson i Prinrip1e.s of' Bacteriology and Imrnurri~ (Arnold. London), p. 1106. 7. van Helvoort, T. (1996) Anz. Sot. Microhiol. News 62, 142-145. 8. Kellenberger. E. (1995) FEMS Microhiol. Ret,. 17, 7-24. 9. Merril, C.. Biswas, B.. Carlton, R.. Jensen, N. C., Creed, G. J.. Zullo. S.. Adhya, S. (1996) Proc. hiat/. Acud. Sci. USA 93, 31X8-3192. IO. Geizr, M. R., Trigg, M. E. & Merril, C. R. (1973) h'ature (Low dortj 246, 22 l-123. Il. Cirillo, J. D.. Falkow, S. &Tompkins. L. S. (19Y4) Infect. 1mmtm 62, 3254-3261. 12. Merril, C. R.. Friedman, T. B., Attallah, A.. Geier, M. R.. Krell, K. & Yarkin, R. (1972) 1,~ Vitro 8, 91-93. 13. Tudor, J. J., McCann, M. P. & Acrich. 1. A. (1990) .I. Bumrio/. 172, 2321-2326. 14. Tomasz. A. (1994) hi. E~rgl. J. &ff. 330, 1247-1251. 15, d'Herelle. F. (1936) The Racteriophuge and Ifs Behavior (Williams & Wilkins, Baltimore), translated by Smith, G. H., p. 629. 16. Erskine, J. M. (1973) Can. J. Microhiol. 19, 837-835. 17. Alippi, A. M. (1989) Microbiologin 5, 35-43. 1X. Tinsley. T. W. (1979) Annu. Ret'. Entomol. 24, 63-87. 19. Kirschbaum, J. B. (1985) Annu. Ret,. Entomol. 30, 51-70. 70. Wang, P. & Nuss, D. L. (19YS) Proc. Rid. Acud. Sci. USA 92, 11529-l 1533. 21. Ghabrial, S. A. (1994) ildr,. I;irrrs Res. 43, 303-3X8. .w.. 3168 Commentary: Lederherg Proc. Nati. Acad. Sci. USA 93 (1996) What are the most likely targets for the application of phage therapy? We think, first of all. of organisms recalcitrant to the usual antibiotics or species in which high-level resistance has emerged (14) and is being promiscuously disseminated by plasmid vectors. Here some pseudomonads and other oppor- tunistic invaders are notorious. Then there are settings in which individual therapy may be less than feasible, or too costly. If the transmission of cholera or dysentery could but be mitigated. the refugee camps bordering Rwanda might be less terrifying. Yes. d'Herelle had enunciated these dreams (15). and today we are somewhat put off by the anecdotal quality of the evidence that he assembled. Even so. it is ambitious but not preposterous to suggest that newer knowledge might yet engen- der some workable weapons for the medical armamentarium. Moving from pestilence to famine, a more likely arena for early application is in agriculture, to deal with bacterial infestations like citrus canker (Xarzthormrzas cirri) and Erwinia fire blight. There have already been suggestions that the synecology of bacteriophage and bacterial pathogens may account for fluctuations in their outbreaks (16, 17). Genetic engineering has been applied to the refinement of entomopha- gous viruses (18) and of bacteria to produce insect toxins (19) but not yet to bacteriophage control. An almost unknown terrain is occupied by fungal pests. which have the potential to wipe out a year's crop of potato. maize, or wheat. and have done so with historic consequences. Virus-like agents are known in many fungi (20). but they are not (or are not readily) now transmitted by horizontal exogenous cross-infection (21): there would be a worthy challenge to contemporary biotechnology. Hopefully that would also be accompanied by the most prudent inquiry about what might go wrong. but the long-term prospects of earth's food supply; are not so robust that we can afford to ignore such opportumties. 4. 5. 6. 10. 11 12. 13. 14. Ii. 16. 17. 18. I'). 20. 21 Swift. J. (1942) in A New Dictionan, qf Quoturiom on Hutorical Principkt fkorn Ancienr and Modern Sources, ed. Mencken, H. L. (Knopf, New York). p. 1712. Duckworth, D. H. (1976) Racteriol. Ret,. 40, 793-802. Bloom, H. cd. (1988) SinrlairLewisS Arrowwnith, Modem Critical Irlrerpretcrnons (Chelsea House. New York). Sullivan, D. J. (1987) Annu. Rev. Entomol. 32, 49-70. Waksman, S. A. (1954) in 114~ L$e Gth the !Microbes, (Simon & Schuster. New York). p. 364. Wilson, G. S. & Miles, A. A., eds. (1955) Topley & Wilso~`.~ Principles of Racteriologr and Imnz~niry (Arnold. London), p. 1106. van Helvoort, T. (1996) Am. Sot. Microbial. Newt 62, 142-14.5. Kcllenherger, E. (1995) FEMS Microhiol. Rev. 17, 7-24. Merril, C., B&as, B., Carlton. R.. Jensen, N. C., Creed, G. J.. Zullo. S., Adhya. S. (1996) Proc. Nutl. Acad. Sri. tiSA 93, 3188-3192. Geier, M. R., Trig, M. E. & Merril, C. R. (1973) Nature (Lon- don) 246, 27 1-223. Cirillo, J. D., Falkow, S. & Tompkins, L. S. (1994) Infect. fmnw7. 62, 3253-3261. Mcrril, C. R., Friedman, T. B.. Attallah, A., Geier. M. R., Krell, K. & Yarkin. R. (1972) 112 Vitro 8, 91-93. Tudor. J. J.. McCann. M. P. & Acrich. I. A. (1990) J. Bacterial. 172, 2421-2426. Tomasz, A. (1994) IV. Eng[. .I. Med. 330, 1247-1251. d'Herelle. F. (1926) The Bacteriophage and Its Behavior (Williams & Wilkins, Baltimore). translated by Smith. G. H.. p. 629. Erskine. J. M. (1973) Can. J. Mmobiol. 19, 837-845. Alippi. A. M. (1989) Microbiologm 5, 35-43. Tinsley. T. W. (1979) Annu. Rev. Entomol. 24, 63-87. Kirschbaum, J. B. (1985) Annu. Rev. Entomol. 30, 51-70. Wang, P. & Nuss, D. L. (1995) Proc. Natl. Acad. Sci. USA 92, 11520-l 1533. Ghabrial, S. A. (19Y4) AdI,. Virus Res. 43. 303-388.