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MAX LUDWIG HENNING DELBRÃCK 89 ward Kellenberger, to apply his instrument to the study of phage (2, p. 116), while Weigle himself arranged with Max to spend his winters working at Caltech, and subsequently resigned his Geneva professorship for a wholetime Caltech research appointment. Maaloe also embarked on phage research in Copenhagen, and Watson worked with him there during the first year of his Fellowship in Europe in 1950, as well as with the Danish biochemist Herman Kalckar, who had attended the first Phage Course in 1945. Thus, the gospel spread and its proselytes increased in number to discover that they had become members of an integrated, friendly and hospitable international family related by social as well as by intellectual bonds, with Max as their father figure. DNA as Genetic Material Max's early work on the one-step growth curve had shown that, following phage infection of bacterial cells, a latent period of about 20 minutes elapses before the cells begin to burst and liberate a hundred or more progeny particles. Mutation had also been revealed by Salvador Luria as the cause of variation in phage, as well as in bacteria as has already been recounted. Then DelbrÃ¼ck and W. T. Bailey (1946c) and A. D. Hershey independently (13) demonstrated genetic recombination when bacteria were doubly infected with phages that differed in two characters. This was the finding that led, about ten years later, to the ultimate genetic analysis of gene structure by Seymour Benzer (8). However, nothing whatsoever was known about the number or nature of the presumptive precursors inside the infected bacteria during the latent period. As Max remarked in a Harvey Lecture that he was invited to give in 1946, some 30 years after the first description of phage as a bacterial virus, "it should be our first aim to develop a
MAX LUDWIG HENNING DELBRÃCK 90 method of determining the number of virus particles which are present in a bacterial cell at any one moment. Here I, and those who have been associated with me in this work, have to make the first admission of failure" (1946b). Such a method was first developed between 1949 and 1952 by A. H. Doermann (12) who disrupted cells at intervals after infection but failed to find any plaque-forming entities during about the first 12 minutes; thereafter infective intracellular particles began to appear and increased linearly. This "eclipse period" clearly showed that the phage changes its state immediately after infection, while the subsequent linear rather than exponential increase in phage numbers implied that this increase is not due to successive replications of its complete organism but is more compatible with an assembly of its component parts (see 2, p. 79). At this stage it is interesting to note that Niels Bohr's influence and SchrÃ¶dinger's prediction still retained a firm hold on Max's imagination. In an address entitled "A physicist looks at biology," delivered at the thousandth meeting of the Connecticut Academy of Arts and Sciences in 1949, he says, It may turn out that certain features of the living cell, including perhaps even replication, stand in a mutually exclusive relationship to the strict application of quantum mechanics, and that a new conceptual language has to be developed to embrace this situation. The limitation in the applicability of present day physics may then prove to be, not the dead end of our search, but the open door to the admission of fresh views of the matter. Just as we find features of the atom, its stability, for instance, which are not reducible to mechanics, we may find features of the living cell which are not reducible to atomic physics but whose appearance stands in a complementary relationship to those of atomic physics (1949b; also 2, p. 9). In 1952 A. D. Hershey and M. Chase (14) published their famous experiment in which they infected cells with phage
MAX LUDWIG HENNING DELBRÃCK 91 in which the DNA and protein were differentially labelled with radioactive phosphorus and sulphur respectively; they found that the DNA entered the cells but that most of the protein, in the form of empty heads, remained outside. The eclipse was therefore the period during which the phage DNA was replicating and directing the synthesis of nascent phage protein. Thus, it turned out that the genetic material was DNA and that the genetic material alone entered the cell to initiate a new viral generation. As early as 1944, Oswald Avery and his colleagues at the Rockefeller Institute, in New York, had published good biochemical evidence that the "transforming principle" of pneumococci, which transfers the hereditary ability to synthesize a polysaccharide characteristic of one type to bacteria of other types, is highly polymerized DNA. Why, then, did the Phage Group seemingly ignore this obvious clue to the chemical nature of the gene until a member of the group itself came to the same conclusion by a less rigorous experiment? In fact, both Max and Salvador Luria were very interested in Avery's work a considerable time before its publication, visited him at the Rockefeller Institute, and admired him as a person. In mid-1943 Avery wrote a long letter to his brother Roy, who was a microbiologist at Vanderbilt University and knew Max and showed him the letter which explained the results of Oswald's research and suggested, very cautiously, that DNA might be the genetic material (2, p. 180). Although pneumococcal transformation was certainly seen as a very interesting phenomenon by DelbrÃ¼ck and Luria, there were then understandable reasons for failing to recognize its genetic importance. The phenomenon appeared to be uniquely restricted to polysaccharide production by a single bacterial species and seemed remote from the problems that beset phage workers. Moreover, at that time, bacterial
MAX LUDWIG HENNING DELBRÃCK 92 genetics did not exist, while DNA was generally regarded as a "stupid" molecule consisting simply of repeating tetrads of the same nucleotides which could hardly carry complex information; it was not until much later that contamination of transforming preparations with small amounts of protein, then favoured as the most likely genetic material, could be excluded. However, the most cogent reason for failure to appreciate the importance of DNA in transformation was probably that it appeared as a biochemical problem, revealed by biochemical techniques. As Luria has said, "People like DelbrÃ¼ck and myself, not only were we not thinking biochemically, but we were somehowâand probably partly unconsciouslyâreacting negatively to biochemistry .... I don't think we attached great importance to whether the gene was protein or nucleic acid. The important thing for us was that the gene had the characteristics that it had to have" (4, p. 62). But others had sensed the importance of DNA, confirmed by the Hershey- Chase experiment, and were working to elucidate its structureâan enterprise that culminated in the Watson-Crick double helix in 1953, a molecule that embodied all the genetic properties required by the gene (20). As soon as the model structure had been built and seemed right, James Watson revealed it first in a letter to Max (19), who was fascinated and thought it obviously right. Max then wrote to Bohr about the model, saying that he thought it equaled Rutherford's discovery of the nucleus of the atom (1). Thus, as Gunther Stent has commented (18, p. 29), in one respect the Phage Group failed in its mission, for it did not discover the new laws of physics that Bohr and SchrÃ¶dinger had prophesized. There turned out to be no paradox; only the hydrogen bond lay at the heart of the