The Murky Origin of Snow White and Her T-Even Dwarfs

Corresponding author: Stephen T. Abedon, Ohio State University, 1680 University Dr., Mansfield, OH 44906., abedon.1{at}osu.edu (E-mail)

That two distinct kinds of substances—the d'Hérelle substances and the genes—should both possess this most remarkable property of heritable variation or "mutability," each working by a totally different mechanism, is quite conceivable, considering the complexity of protoplasm, yet it would seem a curious coincidence indeed. It would open up the possibility of two totally different kinds of life, working by different mechanisms. On the other hand, if these d'Hérelle bodies were really genes, fundamentally like our chromosome genes, they would give us an utterly new angle from which to attack the gene problem. They are filterable, to some extent isolable, can be handled in test-tubes, and their properties, as shown by their effects on the bacteria, can then be studied after treatment. It would be very rash to call these bodies genes, and yet at present we must confess that there is no distinction known between the genes and them. Hence we cannot categorically deny that perhaps we may be able to grind genes in a mortar and cook them in a beaker after all. Must we geneticists become bacteriologists, physiological chemists, and physicists, simultaneously with being zoologists and botanists? Let us hope so.

H. J. MULLER 1922 (pp. 48–49)

Bacteriophages (phages) are viruses whose hosts are bacteria. We employ the term bacteriophage rather than bacteriovirus because phages were initially characterized by their ability to lyse cultures of bacteria. On macroscopic scales, phage growth can occur as though an invisible creature were eating a culture's bacteria. Consequently, the Greek verb phage (), to eat or devour, was applied to this process in 1917 by Felix d'Hérelle, the French-Canadian co-independent-discoverer and popularizer of bacteriophages (D'HERELLE 1917 ). It was only after years of controversy, however, that phages were broadly accepted for what we now understand them to be, the viruses of bacteria.

The utility of phages nevertheless was immediately obvious to d'Hérelle. Phages kill bacteria. Bacteria cause disease. Therefore phages may be harnessed to combat disease. Phage therapy as a treatment of disease, however, has a controversial history (BURNET 1934 ; STENT 1992 ; SUMMERS 1999 ). This controversy has a number of interacting bases including (i) the difficulties of doing clinical trials, under primitive conditions, with poorly defined and heterogeneous antimicrobials; (ii) the primitive state exhibited by the science of bacteriophagy in its early years (STENT 1963 ); (iii) a lack of emphasis on fundamental research (DELBRUCK 1946A ); and (iv) of no minor consequence, the often dogmatically abrasive style (DUCKWORTH 1976 ; SUMMERS 1999 ) that "caused other workers only to redouble their efforts to show d'Hérelle to be wrong" (STENT 1963 , p. 11).

During the early 1940s bacteriophagy's disarray was brought under control and then reversed through the efforts of Max Delbrück and colleagues, making up the Phage Group (DELBRUCK 1946B ; EDGAR 1982 ; STENT 1982 , STENT 1992 ; CAIRNS et al. 1992 ; see also STENT 1963 , STENT 1982 , for an overview of F. M. Burnet's and M. Schlesinger's earlier contributions). Ironically, Delbrück championed d'Hérelle's "heterodoxical," nonbiochemical approach to phage biology (STENT 1982 ; SUMMERS 1993 ; JUDSON 1996 ), although not d'Hérelle's interest in phage therapy (DELBRUCK 1946B ). More or less simultaneously, the 1940s saw a decline in the fortunes of phage therapy coinciding with the dramatic rise in prominence of chemical antibacterials such as penicillin (STENT 1963 ). However, as the efficacy of antibiotics today declines, phage therapy may be achieving something of a scientific as well as a popular comeback (LEDERBERG 1996 ; LEVIN and BULL 1996 ; RADETSKY 1996 ; BARROW and SOOTHILL 1997 ; ALISKY et al. 1998 ; BARROW et al. 1998 ; HOLZMAN 1998 ; KOERNER 1998 ).

Bacteriophages are useful for more than just killing bacteria. They also serve as easy-to-work-with model organisms, some of whose physiology, genetics, etc., borrows from or mimics the physiology, genetics, etc., of their host or of other organisms, including the viruses of plants and of animals (e.g., BOYD 1956 ; ELLIS 1992 ). Ultimately the genius of the Phage Group was the successful implementation of the idea—expressed by MULLER 1922 in the quote introducing this Perspectives (and again, without reference to Muller, by DELBRUCK 1942 )—that bacteriophages may be used as tools for understanding the basic principles of life (EDGAR 1982 ; STENT 1982 ; CAIRNS et al. 1992 ; CAIRNS 1997 ). Phages thus served as workhorses in the development of the field of molecular genetics (WATSON 1991 ; STENT 1992 ), achieving absolute triumph with the publication of the structure of DNA by WATSON and CRICK 1953 . Watson, literally, was a student of the Phage Group (WATSON 1992 ), investigating phage T2 in particular (WATSON 1950 ). Crick, in turn, would go on to help define the details of the genetic code, using T4 bacteriophages (CRICK et al. 1961 ). The ultimate spawn of these efforts was molecular biology, which, with the power of cloning and DNA sequencing, all but defines modern genetics as well as much of modern biochemistry.

This study attempts, through a scrutinizing of available literature, to clarify the very early scientific histories of three phages, the so-called T-even phages, T2, T4, and T6. These phages served as three of the original seven coliphages popularized by the phage group (DEMEREC and FANO 1945 ; DELBRUCK 1946A ). It may never prove possible to identify, with high confidence, the time, place, and source material for the original isolation of phages T2, T4, and T6. Nevertheless, a better understanding of from where the T-even phages originated has historical significance and is of scientific consequence to those of us interested in the ecology of these organisms.

	THE T PHAGES

TOP THE T PHAGES MURKY ORIGIN OF PHAGES... MURKY ORIGIN OF PHAGE... MURKY ORIGIN OF E.... CONCLUSION LITERATURE CITED

ANDERSON 1992 (p. 73) provides an overview of the founding of the "T-set" (T for type; HERSHEY 1946 ) of lytic bacteriophages of E. coli B:

In the summer of 1944 the phage workers under the influence of Delbrück made an important decision. Previously, almost every investigator who worked with bacteriophages had his own private collection of phages and host bacteria. It was therefore almost futile to compare results of different workers, or even to gather a satisfying amount of information about one system. Delbrück insisted that we concentrate our attention on the activity of a set of seven phages on the same host, the now famous E. coli strain B and its mutants, in nutrient broth at 37°C... The set of approved phages had been collected by DEMEREC and FANO 1945 for their studies of the patterns of mutation of strain B to resistance to the phages.

Public description of this group of phages occurred at least by November of 1944, in a paper by Anderson, Delbrück, and Demerec presented in Chicago to the Electron Microscope Society of America (HEDEN 1951 ; see ANDERSON 1945 for the full reference). Publication occurred in March of 1945, with the manuscript received August 8, 1944 (DEMEREC and FANO 1945 ). "Of the seven, the so-called T-even strains (T2, T4, and T6), which are similar structurally, antigenically, and genetically, proved the most useful for biochemical and genetic studies" (CHAMPE 1963 , p. 87).

From a biological as well as historical perspective, it is likely (and humbling) that phages T2, T4, and T6 were all isolated either from fecal material or from feces-containing sewage. First, the relevant literature, reviewed throughout this study, is most consistent with the isolation of these phages from either of these two possible sources. Second, the biology of these phages is consistent with T-even phages, like their E. coli hosts (e.g., SAVAGEAU 1983 ), doing the majority of their growing within the colons of animals (ABEDON 1989 , ABEDON 1990A , ABEDON 1990B ; KUTTER et al. 1994 ). Third, T-even-like phages are typically isolated either from feces or from sewage (KUTTER et al. 1994 ). Fourth, as noted by BOYD 1956 (p. 84), "Although no specific statement to this effect can be found in the literature, there is little doubt that, like the others [i.e., T₃, T₄, T₅, and T₆], T₁, T₂ and T₇ were isolated from sewage or faeces."

	MURKY ORIGIN OF PHAGES T4 AND T6

TOP THE T PHAGES MURKY ORIGIN OF PHAGES... MURKY ORIGIN OF PHAGE... MURKY ORIGIN OF E.... CONCLUSION LITERATURE CITED

DEMEREC and FANO 1945 (pp. 119–120 and 135) acknowledge the isolation of phages T4 and T6 as follows (absence of "T3" from the second half of quote is as published):

The materials used in our experiments consisted of the same bacterial strain—E. coli B—previously used by LURIA and DELBRUCK 1943 ... The phage strains were indicated as type I to type 7 (TI to T7). TI and T2, with which Dr. Luria supplied us, are the alpha and gamma strains of DELBRUCK and LURIA 1942 and are identical with the P28 and PC strains of Dr. J. Bronfenbrenner (KALMANSON and BRONFENBRENNER 1939 ); T₃, T₄, T₅, and T6 were isolated from a mixture of phages supplied by Dr. Tony L. Rakieten; T₇ was isolated from the standard anti-coli-phage mixture prepared by Dr. W. J. MacNeal... We are grateful to Dr. S. E. Luria for cultures of B bacteria and of TI and T2 phages; to Dr. Tony L. Rakieten, of The Long Island College of Medicine, for a culture of mixed phages from which T₄, T₅, and T6 were isolated.

DELBRUCK 1946A (p. 30) similarly described phages T3 through T6 as having been derived "from mixed virus preparations." From what or where might Rakieten have obtained this mixture of phages?

The evidence suggests that Tony L. Rakieten and her frequent co-author (and husband) Morris L. Rakieten considered sewage to be "an excellent source of bacteriophage of the coli-typhoid group" (RAKIETEN 1932 , p. 808). Indeed, I found no reference to their isolation of phages from feces, but many instances of their phage isolation from sewage (e.g., RAKIETEN and RAKIETEN 1938 , RAKIETEN and RAKIETEN 1943 ; RAKIETEN et al. 1940 ; RAKIETEN and BORNSTEIN 1941 ). Thus, odds are that, when Tony Rakieten supplied Demerec and Fano with "a mixture of phages," that mixture consisted of raw sewage or of a phage lysate originally inoculated with raw sewage (RAKIETEN et al. 1940 ) and grown, perhaps, by using an E. coli B host. Consistently, as noted by BOYD 1956 (p. 84), phages "T₃, T₄, T₅, and T₆ were from a series collected by Rakieten, who isolated his [sic?] phages from sewage."

	MURKY ORIGIN OF PHAGE T2

TOP THE T PHAGES MURKY ORIGIN OF PHAGES... MURKY ORIGIN OF PHAGE... MURKY ORIGIN OF E.... CONCLUSION LITERATURE CITED

Tracing phage T2 back to 1927:
The history of phage T2 is complicated by its many pre- DEMEREC and FANO 1945 name changes. In brief, phage T2 was obtained from Salvador Luria who, for reasons we consider below, called this phage . Again as documented below, in the early 1940s Luria obtained phage from Jacques Bronfenbrenner, who described this phage by using various permutations of the letters PC. The pre-1940s history of phage T2 consequently is of a phage PC, particularly in the hands of Bronfenbrenner.

Bronfenbrenner, for whom Alfred D. Hershey worked in various capacities at Washington University, St. Louis (SUMMERS 1993 ; CAIRNS 1997 ; STAHL 1998 ), employed many phages and hosts over the course of his career (e.g., HETLER and BRONFENBRENNER 1932 ; VARNEY and BRONFENBRENNER 1932 ; also BRONFENBRENNER 1927 ). Unfortunately, Bronfenbrenner was not always careful to name phages or describe phage isolations in his publications. Consequently, tracing Bronfenbrenner's use and ultimately his isolation of phage T2 [a.k.a. PC] is not a simple task. An important clue, however, is presented by BRONFENBRENNER 1933 (p. 730), where phage P.C. is described as "one of the coli-phages in our collection, used in the various experiments in our laboratory for nearly 6 years and invariably found to be pure according to all accepted criteria..." The publication is dated February 8, 1933. That places phage P.C. in the Bronfenbrenner laboratory on or about February 1927. A possible corroboration of this date comes from KALMANSON and BRONFENBRENNER 1939 , who twice mention 1927 as the year Bronfenbrenner performed unpublished experiments that were repeated in 1939 with phage P.C. The next year, 1928, Bronfenbrenner moved from the Rockefeller Institute in New York to Washington University (http://www.microbiology.wustl.edu/dept/history/#early).

The oldest Bronfenbrenner reference to a phage PC/P.C. apparently was in 1932 (BRONFENBRENNER 1932 ). The oldest reference I could find to a phage P.C., however, comes from a pair of 1928 papers (MUCKENFUSS 1928A , MUCKENFUSS 1928B ) by Bronfenbrenner's frequent collaborator, Ralph S. Muckenfuss (BRONFENBRENNER et al. 1926 , BRONFENBRENNER et al. 1927 ; BRONFENBRENNER and MUCKENFUSS 1926 , BRONFENBRENNER and MUCKENFUSS 1927A , BRONFENBRENNER and MUCKENFUSS 1927B ). No indication is made in these or later studies by Bronfenbrenner and Muckenfuss from where or from what phage P.C. was obtained. From what, then, might we infer that Bronfenbrenner isolated his coliphages? Fortunately, Bronfenbrenner supplied us with clues. For example (BRONFENBRENNER 1928 , p. 390), "In order to obtain a new strain of bacteriophage, one usually introduces into a culture of bacteria some material contaminated more or less directly with intestinal contents of higher animals." BURNET 1934 (p. 332) echoes this philosophy. Bronfenbrenner supplied some specific descriptions of phage isolations; although few in number, in all cases these were from feces (BRONFENBRENNER and KORB 1924B , BRONFENBRENNER and KORB 1925A , BRONFENBRENNER and KORB 1925B ; BRONFENBRENNER et al. 1926 ). HERSHEY and BRONFENBRENNER 1935 (p. 453) additionally describe E. coli isolation from "unselected human fecal specimens."

Significantly, I found no reference in a Bronfenbrenner study to the isolation of phages from sewage. Thus, Bronfenbrenner and his co-workers showed a bias toward isolating phages from feces. This tendency is not too surprising, given the great precedent of Felix d'Hérelle's fecal phage isolation (D'HERELLE 1917 ; BRONFENBRENNER 1928 ; DUCKWORTH 1976 ; SUMMERS 1999 ) and a series of papers (I–XII) published by Bronfenbrenner and colleagues, whose titles began with, "Studies on the bacteriophage of d'Hérelle... " (BRONFENBRENNER and KALMANSON 1925 ; BRONFENBRENNER and KORB 1925A , BRONFENBRENNER and KORB 1925B , BRONFENBRENNER and KORB 1925C , BRONFENBRENNER and KORB 1926 ; BRONFENBRENNER et al. 1926 ; BRONFENBRENNER 1927 ; BRONFENBRENNER and MUCKENFUSS 1927B ; HETLER and BRONFENBRENNER 1928 ; MUCKENFUSS and KORB 1928 ; MUCKENFUSS 1928A , MUCKENFUSS 1928B ) plus two others whose titles include d'Hérelle's name (BRONFENBRENNER and KORB 1924A , BRONFENBRENNER and KORB 1924B ). If phage PC was isolated by Bronfenbrenner, then it is likely that this isolation was made from fecal material rather than from sewage.

Deciphering "P.C.":
Bronfenbrenner and others appear to have used the strain designations "P.C." and "PC" interchangeably (e.g., BRONFENBRENNER 1932 , BRONFENBRENNER 1933 ; KALMANSON and BRONFENBRENNER 1942 ). The origin of these initials is not mentioned by KALMANSON and BRONFENBRENNER 1939 , however, nor by any other publication accessible to me. Perhaps P.C. was a person's initials. In 1946, a text called The Bacteriophage: A Historical and Critical Survey of 25 Years Research, authored by Dr. P. C. FLU 1946 , was published posthumously. Flu cites MUCKENFUSS 1928B , which is one of the earliest references to a phage P.C., but there is no indication in either reference that Flu collaborated with Bronfenbrenner's group. Alternatively, P.C. might have possessed functional meaning, abbreviating, for example, phage coli [e.g., "P.C. phage (coli)"; BRONFENBRENNER 1933] or polyvalent-phage coli or phage coli-shiga. Indeed, KALMANSON and BRONFENBRENNER 1943 refer at one point to phage PC as coliphage "PC" and at another to PC as coli PC bacteriophage. BRONFENBRENNER and SULKIN 1937 also use the term coli (P.C.) phage, and MUCKENFUSS 1928A uses the designation P.C. coliphage, despite the polyvalent nature of the phage (see also HERSHEY 1946 ). I speculate on additional possibilities below.

	MURKY ORIGIN OF E. COLI B

TOP THE T PHAGES MURKY ORIGIN OF PHAGES... MURKY ORIGIN OF PHAGE... MURKY ORIGIN OF E.... CONCLUSION LITERATURE CITED

"Bacterium coli" P.C.:
KALMANSON and BRONFENBRENNER 1939 utilized a "B. coli" P.C. This strain is of historical significance for two reasons in addition to sharing its name with phage P.C. First, B. coli P.C., according to ANDERSON 1945 , is the "strain PC of Kalmanson and Bronfenbrenner, `39, and called "B" by Luria and Delbrück, `42." Second, SCHAECHTER and NEIDHARDT 1987 trace the early popularity of E. coli as a model experimental system in part to Bronfenbrenner. Assuming that Anderson is correct, then B. coli P.C./E. coli B is the most famous E. coli strain associated with Bronfenbrenner. Unfortunately, I could find no mention from where Bronfenbrenner obtained B. coli P.C. (but see my speculation below). In addition, there appears to be no reference to this strain in any of the earlier Bronfenbrenner, Kalmanson, or Muckenfuss studies. KALMANSON and BRONFENBRENNER 1939 (p. 206), however, note, "The culture used throughout the work was a strain of colon bacillus (B. coli P.C.) which was known to be free of spontaneous lytic activity over a period of 15 years," thus placing B. coli P.C.'s isolation on or before 1924. Although not by Bronfenbrenner, E. coli K12 was isolated from a stool sample in 1922 (BACHMANN 1996 ).

"Coli Bordet":
At the Paris Institute Pasteur, Elie Wollman worked with an E. coli strain called coli Bordet that was considered identical, in terms of phage susceptibility at least, to the E. coli B strain of Luria and Delbrück (E. WOLLMAN, personal communication). This Paris strain is named for Jules Bordet, who discovered complement and was the winner of the 1919 Nobel Prize in Medicine; founded the Pasteur Institute of Brussels, Belgium; and has the bacterial genus Bordetella named after him. André Gratia is a possible connection between Bordet and Bronfenbrenner. Gratia, a student of Bordet's, had moved to the Rockefeller Institute before 1924 (SUMMERS 1999 ), the presumptive date of Bronfenbrenner's acquisition of B. coli P.C. (above), as well as the date that Bronfenbrenner moved to Rockefeller (http://www.microbiology.wustl.edu/dept/history/#early). Thus, it is possible that coli Bordet and B. coli P.C. are clonally related. Might P.C. therefore stand for Pasteur-coli or for Paris-coli? As I discuss below, however, it is probably unlikely that Luria and Delbrück had Bordet in mind when B. coli PC was renamed E. coli B.

If E. coli B is coli Bordet, then this leads to a bit of irony. Gratia and Bordet played notorious roles as d'Hérelle's nemeses. They denied d'Hérelle's viral explanation for bacteriophages and discovered a codiscoverer of bacteriophages, F. W. TWORT 1915 . Thus, d'Hérelle's bacteriophages became widely known as the Twort-d'Hérelle phenomenon (STENT 1963 ; DUCKWORTH 1976 ; SUMMERS 1999 ). Tony and Morris Rakieten, on the other hand, were post-doctoral fellows in d'Hérelle's Yale laboratory between 1928 and 1933, even inheriting d'Hérelle's Yale phage collection when d'Hérelle left (KUTTER et al. 1994 ; W. C. SUMMERS, personal communication). Through Tony Rakieten, then, phages T4 and T6 (plus T3 and T5) at the very least might claim "academic" descent from the laboratory of Felix d'Hérelle. Thus, metaphorically at least, quite possibly we reenact the historical rivalry between d'Hérelle and Bordet whenever we add phages T3, T4, T5, or T6 to a culture of E. coli B/Bordet.

E. coli B:
Delbrück and Luria apparently employed strain-naming conventions with little concern for strain histories. LURIA 1992 (p. 173), for example, describes the naming of phages T1, T2, and E. coli B as follows:

Delbrück and I adjourned to New York for a 48-hour bout of experimentation in my laboratory at the College of Physicians and Surgeons. I had received from Dr. Bronfenbrenner of St. Louis two coli phages active on the same host: P28, later called , later TI, and PC, later called , later T2. The reason for choosing the names and was that my [Olivetti; LURIA 1984] typewriter had the signs , ß, and ; ß was left out for reasons of symmetry, the common host being called B for bacterium.

Delbrück, however, began naming his B. coli strains "B" as early as 1940 (DELBRUCK 1940 ) and by 1942 (DELBRUCK 1942 , p. 11) had collected a number of so-named bacteria (and similarly named phages): "B₁ and P₁ (ELLIS and DELBRUCK 1939 )," "B₂ and P₂ (DELBRUCK 1940 )," and "B₃ and two viruses, P₃ and P₄ (Delbrück and Luria 1941)." Delbrück and Luria (1941) is indicated as "to be published," but so far as I can tell does not exist. DELBRUCK and LURIA 1942 does exist, however, and is the first study to employ E. coli B, phage , and phage as so named. From the latent periods of phages P₃ and P₄ (DELBRUCK 1942 ) I infer that phage P₃ is DELBRÜCK and LURIA's (1942) phage and that phage P₄ is phage . If so, then the B. coli B₃ of DELBRUCK 1942 and the E. coli B of DELBRUCK and LURIA 1942 are likely synonymous, and T2 apparently was briefly called P₄.

DELBRUCK and LURIA 1942 (p. 112, footnote) note that their "choice of [phage and bacterial] names, an adaptation to our experiments, will presently be justified." Apparently a phage--resistant descendant of their E. coli B they called "A" and a phage--resistant descendant of their E. coli B they called "C." Bacterium A was thus an indicator for only phage , bacterium C an indicator for only phage , with bacterium B an indicator for both. Ultimately, however, DEMEREC and FANO 1945 revived Delbrück's letter-number phage-naming method with the letter T replacing Delbrück's previously employed letter P.

	CONCLUSION

TOP THE T PHAGES MURKY ORIGIN OF PHAGES... MURKY ORIGIN OF PHAGE... MURKY ORIGIN OF E.... CONCLUSION LITERATURE CITED

In approximate order of use (HERSHEY 1946 and above), strain designations for what today we call phage T2 have included P.C., PC, P₄, , and P₉H. P₉H was later called T2H. DEMEREC and FANO's (1945) phage T2 was the phage of Luria, which later would be called phage T2L. Luria's phage , in turn, descended from a phage PC stock that later would be called phage T2K (for Kalmanson). The standardization of phages and phage names was an important early step toward the development of the discipline we now call molecular genetics (ANDERSON 1992 , as quoted above). Perhaps we need look little further than this tortured history of phage T2 to understand the genesis of the Delbrück-influenced desire for a simplification of not just what phages people used, but what they called them.

	ACKNOWLEDGMENTS

Thanks go to Harris Bernstein, who read and commented on earlier versions of this study; to Bill Summers for his impressively informed speculations and gossip; to Susan Delagrange, the grammar goddess, for her help wrestling this manuscript into shape; to Mary Joyce for her help tracking down Elie Wollman; and to Cameron Thomas and Hans-Wolfgang Ackermann, who also read and commented on earlier versions. I thank Gunther Stent and Elie Wollman, who read the manuscript and suggested possible Bordet-E. coli PC and Gratia-Bronfenbrenner connections, respectively.

	LITERATURE CITED

TOP THE T PHAGES MURKY ORIGIN OF PHAGES... MURKY ORIGIN OF PHAGE... MURKY ORIGIN OF E.... CONCLUSION LITERATURE CITED

ABEDON, S. T., 1989  Selection for bacteriophage latent period length by bacterial density: a theoretical examination. Microbiol. Ecol. 18:79-88.

ABEDON, S. T., 1990a  Selection for lysis inhibition in bacteriophage. J. Theor. Biol. 146:501-511[Medline].

ABEDON, S. T., 1990b The Ecology of Bacteriophage T4. Ph.D. Dissertation, University of Arizona.

ALISKY, J., K. ICZKOWSKI, A. RAPOPORT, and N. TROITSKY, 1998  Bacteriophages show promise as antimicrobial agents. J. Infect. 36:5-15[Medline].

ANDERSON, T. F., 1945  On a bacteriolytic substance associated with a purified bacterial virus. J. Cell. Comp. Physiol. 25:1-15.

ANDERSON, T. F., 1992 Electron microscopy of phages, pp. 63–78 in Phage and the Origins of Molecular Biology, edited by J. CAIRNS, G. S. STENT and J. D. WATSON. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.

BACHMANN, B. J., 1996 Derivations and genotypes of some mutant derivatives of Escherichia coli K-12, pp. 2460–2488 in Escherichia coli and Salmonella Typhimurium (Cellular and Molecular Biology, Ed. 2) edited by F. C. NEIDHARDT. ASM Press, Washington, DC.

BARROW, P. A. and J. S. SOOTHILL, 1997  Bacteriophage therapy and prophylaxis: rediscovery and renewed assessment of potential. Trends Genet. 5:268-271.

BARROW, P., M. LOVELL, and A. BERCHIERI, JR., 1998  Use of lytic bacteriophage for control of experimental Escherichia coli septicemia and meningitis in chickens and calves. Clin. Diagn. Lab. Immunol. 5:294-298[Abstract/Free Full Text].

BOYD, J. S. K., 1956  Bacteriophage. Biol. Rev. 31:71-107.

BRONFENBRENNER, J. J., 1927  Studies on the bacteriophage of d'Herelle. VII. On the particulate nature of bacteriophage. J. Exp. Med. 45:873-886[Abstract].

BRONFENBRENNER, J. J., 1928 Virus diseases of bacteria – bacteriophagy, pp. 373–414 in Filterable Viruses, edited by T. M. RIVERS. Williams & Wilkins, Baltimore, MD.

BRONFENBRENNER, J. J., 1932  The heat inactivation of bacteriophages. Proc. Soc. Exp. Biol. Med. 29:802-804.

BRONFENBRENNER, J. J., 1933  True polyvalence of pure bacteriophages. Proc. Soc. Exp. Biol. Med. 30:729-732.

BRONFENBRENNER, J. J. and G. KALMANSON, 1925  Studies on the bacteriophage of d'Herelle. I. Is the lytic principle volatile? J. Exp. Med. 41:73-79.

BRONFENBRENNER, J. J. and C. KORB, 1924a  Is the bacteriophage of d'Herelle volatile? Proc. Soc. Exp. Biol. Med. 21:175-177.

BRONFENBRENNER, J. J. and C. KORB, 1924b  Effect of alcohol on the so-called bacteriophage of d'Herelle. Proc. Soc. Exp. Biol. Med. 21:177-179.

BRONFENBRENNER, J. J. and C. KORB, 1925a  Studies on the bacteriophage of d'Hérelle. II. Effect of alcohol on the bacteriophage of d'Hérelle. J. Exp. Med. 42:419-429[Abstract].

BRONFENBRENNER, J. J. and C. KORB, 1925b  Studies on the bacteriophage of d'Herelle. III. Some of the factors determining the number and size of plaques of bacterial lysis on agar. J. Exp. Med. 42:483-497[Abstract].

BRONFENBRENNER, J. J. and C. KORB, 1925c  Studies on the bacteriophage of d'Herelle. IV. Concerning the oneness of the bacteriophage. J. Exp. Med. 42:821-828[Abstract].

BRONFENBRENNER, J. J. and C. KORB, 1926  Studies on the bacteriophage of d'Herelle. V. Effect of electrolytes on the rate of inactivation of bacteriophage by alcohol. J. Exp. Med. 43:71-86.

BRONFENBRENNER, J. J. and R. S. MUCKENFUSS, 1926  The lysis of dead bacteria by bacteriophage. Proc. Soc. Exp. Biol. Med. 23:633-635.

BRONFENBRENNER, J. J. and R. S. MUCKENFUSS, 1927a  On the filterability of bacteria. Proc. Soc. Exp. Biol. Med. 24:371-372.

BRONFENBRENNER, J. J. and R. S. MUCKENFUSS, 1927b  Studies on the bacteriophage of d'Herelle. VIII. The mechanism of lysis of dead bacteria in the presence of bacteriophage. J. Exp. Med. 45:887-909[Abstract].

BRONFENBRENNER, J. J. and S. E. SULKIN, 1937  An attempt to purify bacteriophage by the procedure of Vinson. J. Infect. Dis. 61:259-263.

BRONFENBRENNER, J. J., R. S. MUCKENFUSS, and C. KORB, 1926  Studies on the bacteriophage of d'Herelle. VI. On the virulence of the overgrowth in the lysed cultures of Bacillus pestis caviæ (M. T. II). J. Exp. Med. 44:607-622.

BRONFENBRENNER, J. J., R. S. MUCKENFUSS, and D. M. HETLER, 1927  The study of intimate mechanism of the lysis of bacteria by bacteriophage. Am. J. Pathol. 3:562-565.

BURNET, F. M., 1934  The bacteriophages. Biol. Rev. Cambr. Philos. Soc. 9:332-350.

CAIRNS, J., 1997  Alfred Hershey (1908–97). Nature 388:130[Medline].

CAIRNS, J., G. STENT and J. D. WATSON, 1992 Phage and the Origins of Molecular Biology. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.

CHAMPE, S. P., 1963  Bacteriophage reproduction. Annu. Rev. Microbiol. 17:87-110[Medline].

CRICK, F. H. C., L. BARNETT, S. BRENNER, and R. J. WATTS-TOBIN, 1961  General nature of the genetic code for proteins. Nature 192:1227-1232[Medline].

DELBRÜCK, M., 1940  The growth of bacteriophage and lysis of the host. J. Gen. Physiol. 23:643-660[Abstract/Free Full Text].

DELBRÜCK, M., 1942  Bacterial viruses (bacteriophages). Adv. Enzymol. 2:1-32.

DELBRÜCK, M., 1946a  Bacterial viruses or bacteriophages. Biol. Rev. 21:30-40.

DELBRÜCK, M., 1946b  Experiments with bacterial viruses (bacteriophages). Harvey Lect. 41:161-187.

DELBRÜCK, M. and S. E. LURIA, 1942  Interference between bacterial viruses. I. Interference between two bacterial viruses acting upon the same host, and the mechanism of virus growth. Arch. Biochem. 1:111-141.

DEMEREC, M. and U. FANO, 1945  Bacteriophage-resistant mutants in Escherichia coli.. Genetics 30:119-136[Free Full Text].

DUCKWORTH, D. H., 1976  "Who discovered bacteriophage? Bacteriol. Rev. 40:793-802[Free Full Text].

EDGAR, R. S., 1982  Max Delbrück. Annu. Rev. Genet. 16:501-505[Medline].

ELLIS, E., 1992 Bacteriophage: one-step growth, pp. 56–62 in Phage and the Origins of Molecular Biology, edited by J. CAIRNS, G. S. STENT and J. D. WATSON. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.

ELLIS, E. L. and M. DELBRÜCK, 1939  The growth of bacteriophage. J. Gen. Physiol. 22:365-384[Abstract/Free Full Text].

FLU, P. C., 1946 The Bacteriophage: A Historical and Critical Survey of 25 Years Research. Universitaire Pers Leiden, Leiden.

HEDÉN, C.-G., 1951  Studies of the infection of E. coli B with the bacteriophage T2. Acta Pathol. Microbiol. Scand. Suppl. 8:1-126.

D'HÉRELLE, F., 1917  Sur un microbe invisible antagoniste des bacilles dysentériques. C. R. Acad. Sci. Ser. D 165:373.

HERSHEY, A. D., 1946  Mutation of bacteriophage with respect to type of plaque. Genetics 31:620-640[Free Full Text].

HERSHEY, A. D. and J. J. BRONFENBRENNER, 1935  Dissociation and lactase activity in slow lactose-fermenting bacteria of intestinal origin. J. Bacteriol. 31:453-464.

HETLER, D. M. and J. J. BRONFENBRENNER, 1928  Studies on the bacteriophage of d'Hérelle. IX. Evidence of hydrolysis of bacterial protein during lysis. J. Exp. Med. 48:269-275[Abstract].

HETLER, D. M. and J. J. BRONFENBRENNER, 1932  Further studies on the mechanism of transmissible lysis of bacteria. Proc. Soc. Exp. Biol. Med. 29:806-808.

HOLZMAN, D., 1998  Reassessment of medicinal phage .. spurs companies to study therapeutic uses. ASM News 64:620-623.

JUDSON, H. F., 1996 The Eighth Day of Creation: Makers of the Revolution in Biology. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.

KALMANSON, G. and J. J. BRONFENBRENNER, 1939  Studies on the purification of bacteriophage. J. Gen. Physiol. 23:203-228[Abstract/Free Full Text].

KALMANSON, G. M. and J. J. BRONFENBRENNER, 1942  Evidence of serological heterogeneity of polyvalent "pure line" bacteriophage. J. Immunol. 45:13-19.

KALMANSON, G. M. and J. J. BRONFENBRENNER, 1943  Restoration of activity of neutralized biologic agents by removal of the antibody with papain. J. Immunol. 47:387-407.

KOERNER, B. I., 1998 Return of a killer. U.S. News World Rep. Nov. 2, 51–52.

KUTTER, E., E. KELLENBERGER, K. CARLSON, S. EDDY, J. NEITZEL et al., 1994 Effects of bacterial growth conditions and physiology on T4 infection, pp. 406–418 in The Molecular Biology of Bacteriophage T4, edited by J. D. KARAM. ASM Press, Washington, DC.

LEDERBERG, J., 1996  Smaller fleas .. ad infinitum: therapeutic bacteriophage redux. Proc. Natl. Acad. Sci. USA 93:3167-3168[Abstract/Free Full Text].

LEVIN, B. R. and J. J. BULL, 1996  Phage therapy revisited: the population biology of a bacterial infection and its treatment with bacteriophage and antibiotics. Am. Nat. 147:881-898.

LURIA, S. E., 1984 A Slot Machine, a Broken Test Tube: An Autobiography. Harper & Row, New York.

LURIA, S. E., 1992 Mutations of bacteria and of bacteriophage, pp. 173–179 in Phage and the Origins of Molecular Biology, edited by J. CAIRNS, G. S. STENT and J. D. WATSON. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.

LURIA, S. E. and M. DELBRÜCK, 1942  Interference between inactivated bacterial virus and active virus of the same strain and of a different strain. Arch. Biochem. Biophys. 1:207-218.

LURIA, S. E. and M. DELBRÜCK, 1943  Mutations of bacteria from virus sensitivity to virus resistance. Genetics 28:491-511[Free Full Text].

MUCKENFUSS, R. S., 1928a  Studies on the bacteriophage of d'Hérelle. XI. An inquiry into the mode of action of antibacteriophage serum. J. Exp. Med. 48:709-722[Abstract].

MUCKENFUSS, R. S., 1928b  Studies on the bacteriophage of d'Hérelle. XII. Concerning the production of phage from bacterial cultures. J. Exp. Med. 48:723-729[Abstract].

MUCKENFUSS, R. S. and C. KORB, 1928  Studies on the bacteriophage of d'Hérelle. X. Toxin production by normal and by phage-resistant shiga dysentery bacilli. J. Exp. Med. 48:277-283[Abstract].

MULLER, H. J., 1922  Variation due to change in the individual gene. Am. Nat. 56:32-50.

RADETSKY, P., 1996  The good virus: the use of bacteriophages to fight antibiotic-resistant bacterial diseases. Discover 17(11):50-58.

RAKIETEN, M. L., 1932  Studies with staphylococcus bacteriophage. I. The preparation of polyvalent staphylococcus bacteriophage. Yale J. Biol. Med. 4:807-818.

RAKIETEN, M. L. and S. BORNSTEIN, 1941  Influence of certain bacteriophages on the H antigen of Salmonella poona and E. typhi.. Proc. Soc. Exp. Biol. Med. 48:359-361.

RAKIETEN, M. L. and T. L. RAKIETEN, 1938  The inactivation of "pure line" phages by bacterial extracts and the loss of phage types in vivo. Yale J. Biol. Med. 10:191-208.

RAKIETEN, M. L., A. H. EGGERTH, and T. L. RAKIETEN, 1940  Studies with bacteriophages active against mucoid strains of bacteria. J. Bacteriol. 40:529-545[Free Full Text].

RAKIETEN, T. L. and M. L. RAKIETEN, 1943  Bacteriophagy in the developing chick embryo. J. Bacteriol. 45:477-484[Free Full Text].

SAVAGEAU, M. A., 1983  Escherichia coli habitats, cell types, and molecular mechanisms of gene control. Am. Nat. 122:732-744.

SCHAECHTER, M., and F. C. NEIDHARDT, 1987 Introduction, pp. 1–2 in Escherichia coli and Salmonella typhimurium (Cellular and Molecular Biology), edited by F. C. NEIDHARDT. ASM Press, Washington, DC.

STAHL, F. W., 1998  Hershey. Genetics 149:1-6[Free Full Text].

STENT, G., 1963 Molecular Biology of Bacterial Viruses. W. H. Freeman, San Francisco.

STENT, G., 1982  MAX DELBRÜCK, 1906–1981. Genetics 101:1-16.

STENT, G. S., 1992 Introduction: waiting for the paradox, pp. 3–8 in Phage and the Origins of Molecular Biology, edited by J. CAIRNS, G. S. STENT and J. D. WATSON. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.

SUMMERS, W. C., 1993  How bacteriophage came to be used by the Phage Group. J. Hist. Biol. 26:255-267[Medline].

SUMMERS, W. C., 1999 Felix d'Herelle and the Origins of Molecular Biology. Yale University Press, New Haven, CT.

TWORT, F. W., 1915  An investigation on the nature of the ultra-microscopic viruses. Lancet 189:1241-1243.

VARNEY, P. L. and J. J. BRONFENBRENNER, 1932  Effects of "K" medium on the filterability of bacteria. Proc. Soc. Exp. Biol. Med. 29:804-806.

WATSON, J. D., 1950  The properties of X-ray inactivated bacteriophage. I. Inactivation by direct effect. J. Bacteriol. 60:697-718[Free Full Text].

WATSON, J. D., 1991  Salvador E. Luria (1912–1991). Nature 350:113[Medline].

WATSON, J. D., 1992 Growing up in the phage group, pp. 239–245 in Phage and the Origins of Molecular Biology, edited by J. CAIRNS, G. S. STENT and J. D. WATSON. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.

WATSON, J. D. and F. H. C. CRICK, 1953  A structure for deoxyribose nucleic acid. Nature 171:737[Medline].

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