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© 2001 Nature Publishing Group http://structbio.nature.com news and views © 2001 Nature Publishing Group http://structbio.nature.com that interfering with tyrosine kinase signaling pathways will be an important anticancer therapeutic strategy. Thus, efforts invested to optimize new classes of inhibitors, such as that described by Parang et al.5, should yield high dividends. W. Todd Miller is in the Department of Physiology and Biophysics, State University of New York at Stony Brook, Stony Brook, New York 11794-8661, USA. email: [email protected] 1. Hunter, T. Cell 100, 113–127 (2000). 2. Levitski, A. Pharmacol. Ther. 82, 231–239 (1999). 3. Lawrence, D.S. & Niu, J. Phamacol. Ther. 77, 81–114 (1998). 4. Druker, B.J. & Lydon, N.B. J. Clin. Invest. 105, 3–7 (2000). 5. Parang, K. et al. Nature Struct. Biol. 8, 37–41 (2001). 6. Taylor, S.S. & Radzio-Andzelm, E. Structure 2, 345–355 (1994). 7. Schlessinger, J. Cell 103, 211–225 (2000). 8. Hubbard, S.R., Wei, L., Ellis, L. & Hendrickson, W.A. Nature 372, 746–753 (1994). 9. Hubbard, S.R. EMBO J. 16, 5572–5581 (1997). 10. Lienhard, G.E. & Secemski, I.I. J. Biol. Chem. 248, 1121–1123 (1973). 11. Hampton, A., Hai, T.T., Kappler, F. & Chawla, R,R. J. Med. Chem. 25, 801–805 (1982). 12. Jencks, W.P. Proc. Natl. Acad. Sci. USA 78, 4046–4050 (1981). 13. Ablooglu, A.J. et al. J. Biol. Chem. 275, 30394–30398 (2000). 14. Mildvan, A.S. Proteins Struct. Func. Genet. 29, 401–416 (1997). 15. Scheffzek, K., Kliche, W., Wiesmüller, L. & Reinstein, J. Biochemistry 35, 9716–9727 (1996). 16. Songyang, Z. et al. Nature 373, 536–539 (1995). 17. Sondhi, D., Xu, W., Songyang, Z., Eck, M.J. & Cole, P.A. Biochemistry 37, 165–172 (1998). 18. Pawson, T. & Scott, J.D. Science 278, 2075–2080 (1997). 19. Profit, A.A., Lee, T.R. & Lawrence, D.S. J. Am. Chem. Soc. 121, 280–283 (1999). 20. Maly, D.J., Choong, I.C. & Ellman, J.A. Proc. Natl. Acad. Sci. USA 97, 2419–2424 (2000). book review Hershey heaven Angela N. H. Creager We can sleep later: Alfred D. Hershey and the origins of molecular biology, Edited by Franklin W. Stahl. Published by Cold Spring Harbor Press, Cold Spring Harbor, New York, USA; 2000. 357 pages, US $39. ISBN 0-87969-567-6. When Alan Garen asked Alfred Hershey for his idea of scientific happiness, Hershey replied, “To have one experiment that works, and keep doing it all the time”1. The first generation of molecular biologists referred to this as “Hershey heaven.” Both Hershey’s wit and his scientific achievements receive their due in We can sleep later: Alfred D. Hershey and the origins of molecular biology. This volume, edited by Franklin Stahl, pays tribute to Hershey through essays and reminiscences by scientists who knew him and includes a selection of his writings. The recognition, as several contributors point out, is long overdue. Hershey, who died in 1997 at the age of 88, is best known as one of the three founders of the ‘phage group’. He shared the Nobel Prize in 1969 with Max Delbrück and Salvador Luria for their pioneering work establishing bacteriophage as the premier model system for molecular genetics. Yet Hershey’s reticence kept him out of the public spotlight, and his research career at Cold Spring Harbor meant that he taught few students. The marvelous reflections on science, which he often included in his yearly reports as director of the Carnegie Institution’s Carnegie Research Unit, reached a small audience. Consequently, this engaging volume introduces us to a little-known Hershey, filling in the details beyond his famous 1952 experiment and his quip about experimental bliss. 18 Hershey’s versatility with genetic and chemical methods was remarkable even for the time. He and Raquel Rotman provided the first linkage map of a virus, bacteriophage T2, in 1949 (ref. 2). Three years later, the ‘Hershey-Chase’ experiment (performed with technician Martha Chase) provided decisive biochemical evidence that nucleic acids are the hereditary material3. Using a Waring blender to separate radiolabeled phage that had infected bacteria from the phage ‘ghosts’ which remained on the outside of the cells, Hershey and Chase showed that 32P-labeled nucleic acids entered the cells whereas 35S-labeled proteins largely remained on the outside. Hershey’s new evidence for the genetic role of nucleic acids in virus reproduction came as a surprise, despite the experiment published by Avery, MacLeod and McCarty in 1944 showing that DNA could genetically alter bacteria4. According to several contributors to the book, even Hershey expected his experiment to confirm that genes were composed of proteins. James Watson credits Hershey’s results with providing the impetus for him to pursue the structure of DNA. The experiment’s significance was reinforced by its pedagogical value; the HersheyChase experiment became a staple of molecular biology textbooks. The blender experiment exemplified Hershey’s ingenuity but did not exhaust it. In 1957 Hershey turned his attention to nucleic acid structure, using chromatography and ultracentrifugation to ascertain the size and shape of viral DNA. He demonstrated that the chromosome of phage (using T2 and λ) consisted of a single double-stranded molecule. Hershey’s further characterization of the λ chromosome showed that it had “sticky ends” (in his apt phrasing). Hershey’s adeptness as an editor matched his elegant experimentation. The title of the volume is taken from a letter he wrote to contributors to Bacteriophage λ, published in 1971 (ref. 5). Urging the authors of the 52 essays to complete and return their manuscripts, he ended the letter: “We can sleep later”. The subtitle of We can sleep later invokes a longstanding historical debate with respect to the origins of molecular biology. nature structural biology • volume 8 number 1 • january 2001 © 2001 Nature Publishing Group http://structbio.nature.com © 2001 Nature Publishing Group http://structbio.nature.com book review The 1966 Phage and the origins of molecular biology6, edited by John Cairns, Gunther Stent, and James Watson, offered a genealogy of molecular biology with Delbrück as founding father. The book’s implicit message that molecular biology derived from the phage group drew fire from some. John Kendrew argued that structural biologists (such as those in his unit at Cambridge) had also played a crucial role in the founding of molecular biology7. Gunther Stent subsequently offered a conciliatory view of the origins of molecular biology that combined the ‘informational’ school of phage genetics with the ‘structural’ school of X-ray crystallographers, a meeting of the minds that was conveniently personified by Watson and Crick8. This enlarged family tree still did not satisfy everyone; Origins of molecular biology: A tribute to Jacques Monod9, stressed the early importance of French microbiologists. Nonetheless, historical interpretations that emphasized these various ‘origins’ tended to demarcate molecular biology firmly from pre-existing fields, especially biochemistry (Delbrück famously disparaged biochemistry). By all these accounts, Hershey makes an odd revolutionary. He is described by friends as a “biochemist’s biochemist” as well as a pioneering molecular geneticist. His research defied any dichotomy between informational and structural approaches, and he retained a skeptical attitude towards the supremacy of nucleic acids. Attention to Hershey as one of the original molecular biologists complicates the story, showing the limitations of views that emphasize a single approach, dogma, or charismatic leader. By portraying a trailblazing biologist who combined structural, biochemical, and genetic methods in his quest to understand life at the molecular level, We can sleep later cautions us to keep a broad view of molecular biology’s past — and its future. Angela N. H. Creager is in the Department of History and Program in History of Science, Princeton University, Princeton, New Jersey 08544, USA. email: [email protected] 1. As quoted in Judson, H.F. The eighth day of creation: The makers of the revolution in biology, 275 (Simon and Schuster, New York; 1979). 2. Hershey, A.D. & Rotman, R. Genetics 34, 44–71 (1949). 3. Hershey, A.D. & Chase, M. J. Gen. Physiol. 36, 39–56 (1952). 4. Avery, O.T., MacLeod, C.M. & McCarty, M. J. Exp. Med. 79, 137–158 (1944). 5. Hershey, A.D., ed. The bacteriophage lambda. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York; 1971). 6. Cairns, J., Stent, G.S. & Watson, J.D. Phage and the origins of molecular biology. (Cold Spring Harbor Press, Cold Spring Harbor, New York; 1966). 7. Kendrew, J. Sci. Am. 216, 141–43 (1967). 8. Stent, G.S. Science 160, 390–395 (1968). 9. Lwoff, A. & Ullmann, A. Origins of molecular biology: A tribute to Jacques Monod. (Academic Press, New York; 1979). history Phage facts Often the simplest experiments lead to the most remarkable insights. So it was with the famous fluctuation experiments of Luria and Delbrück and the Waring blender experiments of Hershey and Chase for which they were awarded the Nobel Prize in Physiology or Medicine in 1969. While the results of these experiments are permanently etched into every first year biology student’s brain, it is worth recalling what was known at the time these experiments were conducted and the conclusions the authors drew. In the early 20th century, the role of chance mutations in the genetic variation of higher organisms was generally accepted. However, bacterial cultures seemed to be plastic. Exposed to adverse conditions, cultures of bacteria could give rise to resistant variants that remained resistant “to the action of the virus even if subcultured through many generations in the absence of the virus”1. At the time, many scientists believed that the “virus by direct action induced the resistant variants”1. Others believed that the “resistant bacterial variants are produced by mutation in the culture prior to the addition of virus. The virus merely brings the variants into prominence by eliminating all sensitive bacteria”1. These two alternative theories — induced immunity and selection of spontaneous mutations — were rigorously tested both theoretically and experimentally by Max Delbrück and Salvadore E. Luria, respectively, in 1943. The two hypotheses lead to different predictions regarding the distribution of resistant bacteria in a series of parallel cultures. The hypothesis of acquired or induced immunity predicts that the number of mutants in each culture would be clustered around the mean with little variation between cultures. According to the selection hypothesis, resistant bacteria could arise at any point in the life of the culture. This would result in very different numbers of mutants per culture and thus the variability from culture to culture would be high. Luria found that in every experiment the “fluctuation of the numbers of resistant bacteria is tremendously higher than could be accounted for by the sampling errors, in striking contrast to the results of plating from the same culture and in conflict with the expectations from the hypothesis of acquired immunity”1. Luria and Delbrück concluded that the “resistance to virus is due to a heritable change of the bacterial cell which occurs independently of the action of the virus”1. In other words, the mutation was there before the virus was added. nature structural biology • volume 8 number 1 • january 2001 Later, when Alfred D. Hershey and Martha Chase began their experiments, little was known about the early steps of phage infection. What was known was that after the phage adsorbed to the bacteria there was a latent period of ∼10 minutes after which time infectious virus particles were made, ultimately leading to host cell lysis and phage release. Hershey and Chase reasoned that if they knew the fate of the viral protein and the nucleic acid at the beginning of phage infection they would understand more about the nature of those early steps. They labeled the phage with either 35S or 32P, allowed them to adsorb to the bacteria and then the cells were separated from the unadsorbed material by centrifugation. The cells were resuspended and the suspension was spun in a Waring blender to separate the phage from the infected bacteria. They found that ∼80% of the 35S label was removed from the bacteria whereas only ∼20% of the 32P label was removed. They concluded that “most of the phage DNA enters the cell, and a residue containing at least 80% of the sulfur-containing protein of the phage remains at the cell surface”2. Together with the 1944 experiments of Oswald Avery3 in which nucleic acid, not protein, was shown to have “transforming” properties, these findings persuaded most scientists that DNA carried the genetic information. Curiously, however, Hershey himself remained skep19