Meanings in search of experiments and vice-versa: The invention of allosteric regulation in Paris and Berkeley, 1959-1968

Historical Studies in the Physical and Biological Sciences

Volumn 27, Issue 1, 1996, Pages 1-88

  Creager, Angela N H ^a   Gaudillière, Jean Paul ^b  

^a PRINCETON UNIVERSITY   (United States)

^b HÔPITAL NECKER ENFANTS MALADES   (France)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 4243054010     PISSN: 08909997     EISSN: None     Source Type: Journal    
DOI: 10.2307/27757769     Document Type: Review

References (258)

1. See Agnes Ullman, "Being around," in André Lwoff and Agnes Ullman, eds., Origins of molecular biology: A tribute to Jacques Monod (New York, 1979), 167. This statement of Monod's has been popularized by Horace Judson (among others), who entitled his chapter on allosteric regulation, "I have discovered the second secret of life." The eighth day of creation: The makers of the revolution in biology (New York, 1979).
2. See Agnes Ullman, "Being around," in André Lwoff and Agnes Ullman, eds., Origins of molecular biology: A tribute to Jacques Monod (New York, 1979), 167. This statement of Monod's has been popularized by Horace Judson (among others), who entitled his chapter on allosteric regulation, "I have discovered the second secret of life." The eighth day of creation: The makers of the revolution in biology (New York, 1979).
3. Robert L. Baldwin, in Lwoff and Ullman, eds. (ref. 1), 203.
4. Henri Buc, "Mother nature and the design of a regulatory enzyme," in Lwoff and Ullman, eds. (ref. 1), 218.
5. David Gooding, Experiment and the making of meaning: Human agency in scientific observation and experiment (Boston, 1990).
6. "Pasteurian" refers to techniques developed by Pasteur and "Pastorian" to Pasteur's collaborators or to the scientific community working at the Pasteur Institute. See Claire Salomon-Bayet, Pasteur et la revolution pastorienne (Paris, 1986).
7. On experimental systems, see Robert Kohler, "Systems of production: Drosophila, Neurospora, and biochemical genetics," HSPS, 22:1 (1991), 87-130; Hans-Jörg Rheinberger, "Experiment, difference, and writing: I. Tracing protein synthesis, II. The laboratory production of transfer RNA," Studies in history and philosophy of science, 23 (1992), 305-331, and 389-422; Jean-Paul Gaudillière, "Wie man Labormodelle für Krebsentstehung konstruiert," in Objeckte, Differenzen, Konjunkturen: Experimentalsysteme im historischen Kontext, eds. Michael Hagner, Hans-Jörg Rheinberger, and Bettina Wahrig-Schmidt (Berlin, 1994), 233-255. On recent interest in the "material production of matter of facts:" Steven Shapin and Simon Schaffer, Leviathan and the air pump: Hobbes, Boyle, and the experimental life (Princeton, 1985); David Gooding, Trevor Pinch, and Simon Schaffer, The uses of experiment: Studies in the natural sciences (Cambridge, 1988); Adele Clarke and Joan Fujimura, eds., The right tools for the job: At work in twentieth-century sciences (Princeton, 1992). A critique of this trend is given by Frederic L. Holmes, "Do we understand historically how experimental knowledge is acquired?," History of science, 30 (1992), 119-136.
8. On experimental systems, see Robert Kohler, "Systems of production: Drosophila, Neurospora, and biochemical genetics," HSPS, 22:1 (1991), 87-130; Hans-Jörg Rheinberger, "Experiment, difference, and writing: I. Tracing protein synthesis, II. The laboratory production of transfer RNA," Studies in history and philosophy of science, 23 (1992), 305-331, and 389-422; Jean-Paul Gaudillière, "Wie man Labormodelle für Krebsentstehung konstruiert," in Objeckte, Differenzen, Konjunkturen: Experimentalsysteme im historischen Kontext, eds. Michael Hagner, Hans-Jörg Rheinberger, and Bettina Wahrig-Schmidt (Berlin, 1994), 233-255. On recent interest in the "material production of matter of facts:" Steven Shapin and Simon Schaffer, Leviathan and the air pump: Hobbes, Boyle, and the experimental life (Princeton, 1985); David Gooding, Trevor Pinch, and Simon Schaffer, The uses of experiment: Studies in the natural sciences (Cambridge, 1988); Adele Clarke and Joan Fujimura, eds., The right tools for the job: At work in twentieth-century sciences (Princeton, 1992). A critique of this trend is given by Frederic L. Holmes, "Do we understand historically how experimental knowledge is acquired?," History of science, 30 (1992), 119-136.
9. On experimental systems, see Robert Kohler, "Systems of production: Drosophila, Neurospora, and biochemical genetics," HSPS, 22:1 (1991), 87-130; Hans-Jörg Rheinberger, "Experiment, difference, and writing: I. Tracing protein synthesis, II. The laboratory production of transfer RNA," Studies in history and philosophy of science, 23 (1992), 305-331, and 389-422; Jean-Paul Gaudillière, "Wie man Labormodelle für Krebsentstehung konstruiert," in Objeckte, Differenzen, Konjunkturen: Experimentalsysteme im historischen Kontext, eds. Michael Hagner, Hans-Jörg Rheinberger, and Bettina Wahrig-Schmidt (Berlin, 1994), 233-255. On recent interest in the "material production of matter of facts:" Steven Shapin and Simon Schaffer, Leviathan and the air pump: Hobbes, Boyle, and the experimental life (Princeton, 1985); David Gooding, Trevor Pinch, and Simon Schaffer, The uses of experiment: Studies in the natural sciences (Cambridge, 1988); Adele Clarke and Joan Fujimura, eds., The right tools for the job: At work in twentieth-century sciences (Princeton, 1992). A critique of this trend is given by Frederic L. Holmes, "Do we understand historically how experimental knowledge is acquired?," History of science, 30 (1992), 119-136.
10. On experimental systems, see Robert Kohler, "Systems of production: Drosophila, Neurospora, and biochemical genetics," HSPS, 22:1 (1991), 87-130; Hans-Jörg Rheinberger, "Experiment, difference, and writing: I. Tracing protein synthesis, II. The laboratory production of transfer RNA," Studies in history and philosophy of science, 23 (1992), 305-331, and 389-422; Jean-Paul Gaudillière, "Wie man Labormodelle für Krebsentstehung konstruiert," in Objeckte, Differenzen, Konjunkturen: Experimentalsysteme im historischen Kontext, eds. Michael Hagner, Hans-Jörg Rheinberger, and Bettina Wahrig-Schmidt (Berlin, 1994), 233-255. On recent interest in the "material production of matter of facts:" Steven Shapin and Simon Schaffer, Leviathan and the air pump: Hobbes, Boyle, and the experimental life (Princeton, 1985); David Gooding, Trevor Pinch, and Simon Schaffer, The uses of experiment: Studies in the natural sciences (Cambridge, 1988); Adele Clarke and Joan Fujimura, eds., The right tools for the job: At work in twentieth-century sciences (Princeton, 1992). A critique of this trend is given by Frederic L. Holmes, "Do we understand historically how experimental knowledge is acquired?," History of science, 30 (1992), 119-136.
11. On experimental systems, see Robert Kohler, "Systems of production: Drosophila, Neurospora, and biochemical genetics," HSPS, 22:1 (1991), 87-130; Hans-Jörg Rheinberger, "Experiment, difference, and writing: I. Tracing protein synthesis, II. The laboratory production of transfer RNA," Studies in history and philosophy of science, 23 (1992), 305-331, and 389-422; Jean-Paul Gaudillière, "Wie man Labormodelle für Krebsentstehung konstruiert," in Objeckte, Differenzen, Konjunkturen: Experimentalsysteme im historischen Kontext, eds. Michael Hagner, Hans-Jörg Rheinberger, and Bettina Wahrig-Schmidt (Berlin, 1994), 233-255. On recent interest in the "material production of matter of facts:" Steven Shapin and Simon Schaffer, Leviathan and the air pump: Hobbes, Boyle, and the experimental life (Princeton, 1985); David Gooding, Trevor Pinch, and Simon Schaffer, The uses of experiment: Studies in the natural sciences (Cambridge, 1988); Adele Clarke and Joan Fujimura, eds., The right tools for the job: At work in twentieth-century sciences (Princeton, 1992). A critique of this trend is given by Frederic L. Holmes, "Do we understand historically how experimental knowledge is acquired?," History of science, 30 (1992), 119-136.
12. On experimental systems, see Robert Kohler, "Systems of production: Drosophila, Neurospora, and biochemical genetics," HSPS, 22:1 (1991), 87-130; Hans-Jörg Rheinberger, "Experiment, difference, and writing: I. Tracing protein synthesis, II. The laboratory production of transfer RNA," Studies in history and philosophy of science, 23 (1992), 305-331, and 389-422; Jean-Paul Gaudillière, "Wie man Labormodelle für Krebsentstehung konstruiert," in Objeckte, Differenzen, Konjunkturen: Experimentalsysteme im historischen Kontext, eds. Michael Hagner, Hans-Jörg Rheinberger, and Bettina Wahrig-Schmidt (Berlin, 1994), 233-255. On recent interest in the "material production of matter of facts:" Steven Shapin and Simon Schaffer, Leviathan and the air pump: Hobbes, Boyle, and the experimental life (Princeton, 1985); David Gooding, Trevor Pinch, and Simon Schaffer, The uses of experiment: Studies in the natural sciences (Cambridge, 1988); Adele Clarke and Joan Fujimura, eds., The right tools for the job: At work in twentieth-century sciences (Princeton, 1992). A critique of this trend is given by Frederic L. Holmes, "Do we understand historically how experimental knowledge is acquired?," History of science, 30 (1992), 119-136.
13. On experimental systems, see Robert Kohler, "Systems of production: Drosophila, Neurospora, and biochemical genetics," HSPS, 22:1 (1991), 87-130; Hans-Jörg Rheinberger, "Experiment, difference, and writing: I. Tracing protein synthesis, II. The laboratory production of transfer RNA," Studies in history and philosophy of science, 23 (1992), 305-331, and 389-422; Jean-Paul Gaudillière, "Wie man Labormodelle für Krebsentstehung konstruiert," in Objeckte, Differenzen, Konjunkturen: Experimentalsysteme im historischen Kontext, eds. Michael Hagner, Hans-Jörg Rheinberger, and Bettina Wahrig-Schmidt (Berlin, 1994), 233-255. On recent interest in the "material production of matter of facts:" Steven Shapin and Simon Schaffer, Leviathan and the air pump: Hobbes, Boyle, and the experimental life (Princeton, 1985); David Gooding, Trevor Pinch, and Simon Schaffer, The uses of experiment: Studies in the natural sciences (Cambridge, 1988); Adele Clarke and Joan Fujimura, eds., The right tools for the job: At work in twentieth-century sciences (Princeton, 1992). A critique of this trend is given by Frederic L. Holmes, "Do we understand historically how experimental knowledge is acquired?," History of science, 30 (1992), 119-136.
14. F.L. Holmes' books have provided the benchmark for use of laboratory notebooks in the history of experimental biology. See Frederic Lawrence Holmes, Claude Bernard and animal chemistry: The emergence of a scientist (Cambridge, 1974); Lavoisier and the chemistry of life: An exploration of scientific creativity (Madison, 1985); and particularly Hans Krebs, vol. I, The formation of a scientific life, 1900-1933; vol. II: Architect of intermediary metabolism, 1933-1937 (New York, 1991, 1993). Mirko Grmek's use of Claude Bernard's notebooks in his historical account of Bernard's work also provide an important precedent. See Grmek, Raisonnement expérimental et recherches toxicologiques chez Claude Bernard (Geneva, 1973). Our approach takes inspiration from David Gooding (ref. 4). Most recently, Gerald Geison's The private science of Louis Pasteur (Princeton, 1995) uses laboratory notebooks to stress the difference between actual scientific work and its public presentation.
15. F.L. Holmes' books have provided the benchmark for use of laboratory notebooks in the history of experimental biology. See Frederic Lawrence Holmes, Claude Bernard and animal chemistry: The emergence of a scientist (Cambridge, 1974); Lavoisier and the chemistry of life: An exploration of scientific creativity (Madison, 1985); and particularly Hans Krebs, vol. I, The formation of a scientific life, 1900-1933; vol. II: Architect of intermediary metabolism, 1933-1937 (New York, 1991, 1993). Mirko Grmek's use of Claude Bernard's notebooks in his historical account of Bernard's work also provide an important precedent. See Grmek, Raisonnement expérimental et recherches toxicologiques chez Claude Bernard (Geneva, 1973). Our approach takes inspiration from David Gooding (ref. 4). Most recently, Gerald Geison's The private science of Louis Pasteur (Princeton, 1995) uses laboratory notebooks to stress the difference between actual scientific work and its public presentation.
16. F.L. Holmes' books have provided the benchmark for use of laboratory notebooks in the history of experimental biology. See Frederic Lawrence Holmes, Claude Bernard and animal chemistry: The emergence of a scientist (Cambridge, 1974); Lavoisier and the chemistry of life: An exploration of scientific creativity (Madison, 1985); and particularly Hans Krebs, vol. I, The formation of a scientific life, 1900-1933; vol. II: Architect of intermediary metabolism, 1933-1937 (New York, 1991, 1993). Mirko Grmek's use of Claude Bernard's notebooks in his historical account of Bernard's work also provide an important precedent. See Grmek, Raisonnement expérimental et recherches toxicologiques chez Claude Bernard (Geneva, 1973). Our approach takes inspiration from David Gooding (ref. 4). Most recently, Gerald Geison's The private science of Louis Pasteur (Princeton, 1995) uses laboratory notebooks to stress the difference between actual scientific work and its public presentation.
17. F.L. Holmes' books have provided the benchmark for use of laboratory notebooks in the history of experimental biology. See Frederic Lawrence Holmes, Claude Bernard and animal chemistry: The emergence of a scientist (Cambridge, 1974); Lavoisier and the chemistry of life: An exploration of scientific creativity (Madison, 1985); and particularly Hans Krebs, vol. I, The formation of a scientific life, 1900-1933; vol. II: Architect of intermediary metabolism, 1933-1937 (New York, 1991, 1993). Mirko Grmek's use of Claude Bernard's notebooks in his historical account of Bernard's work also provide an important precedent. See Grmek, Raisonnement expérimental et recherches toxicologiques chez Claude Bernard (Geneva, 1973). Our approach takes inspiration from David Gooding (ref. 4). Most recently, Gerald Geison's The private science of Louis Pasteur (Princeton, 1995) uses laboratory notebooks to stress the difference between actual scientific work and its public presentation.
18. F.L. Holmes' books have provided the benchmark for use of laboratory notebooks in the history of experimental biology. See Frederic Lawrence Holmes, Claude Bernard and animal chemistry: The emergence of a scientist (Cambridge, 1974); Lavoisier and the chemistry of life: An exploration of scientific creativity (Madison, 1985); and particularly Hans Krebs, vol. I, The formation of a scientific life, 1900-1933; vol. II: Architect of intermediary metabolism, 1933-1937 (New York, 1991, 1993). Mirko Grmek's use of Claude Bernard's notebooks in his historical account of Bernard's work also provide an important precedent. See Grmek, Raisonnement expérimental et recherches toxicologiques chez Claude Bernard (Geneva, 1973). Our approach takes inspiration from David Gooding (ref. 4). Most recently, Gerald Geison's The private science of Louis Pasteur (Princeton, 1995) uses laboratory notebooks to stress the difference between actual scientific work and its public presentation.
19. F.L. Holmes' books have provided the benchmark for use of laboratory notebooks in the history of experimental biology. See Frederic Lawrence Holmes, Claude Bernard and animal chemistry: The emergence of a scientist (Cambridge, 1974); Lavoisier and the chemistry of life: An exploration of scientific creativity (Madison, 1985); and particularly Hans Krebs, vol. I, The formation of a scientific life, 1900-1933; vol. II: Architect of intermediary metabolism, 1933-1937 (New York, 1991, 1993). Mirko Grmek's use of Claude Bernard's notebooks in his historical account of Bernard's work also provide an important precedent. See Grmek, Raisonnement expérimental et recherches toxicologiques chez Claude Bernard (Geneva, 1973). Our approach takes inspiration from David Gooding (ref. 4). Most recently, Gerald Geison's The private science of Louis Pasteur (Princeton, 1995) uses laboratory notebooks to stress the difference between actual scientific work and its public presentation.
20. Peter Medawar, The art of the soluble (London, 1967), 151.
21. Susan Leigh Star and James R. Griesemer, "Institutional ecology, 'translations' and boundary objects: Amateurs and professionals in Berkeley's Museum of Vertebrate Zoology." Social studies of science, 19 (1989), 387-420. See also Ilana Löwy, "The strength of loose concepts - boundary concepts, federative experimental strategies and disciplinary growth: The case of immunology," History of science, 30 (1992), 371-396.
22. Susan Leigh Star and James R. Griesemer, "Institutional ecology, 'translations' and boundary objects: Amateurs and professionals in Berkeley's Museum of Vertebrate Zoology." Social studies of science, 19 (1989), 387-420. See also Ilana Löwy, "The strength of loose concepts - boundary concepts, federative experimental strategies and disciplinary growth: The case of immunology," History of science, 30 (1992), 371-396.
23. Correspondence between Arthur B. Pardee and Jacques Monod, Fonds Monod, Archives de l'Institut Pasteur, Paris. In the Monod papers (to which some letters were never deposited), there are copies of sixteen letters from Pardee to Monod and twenty letters from Monod to Pardee just during the period between September 1958 and December 1959.
24. Jean-Paul Gaudillière, "How biochemical regulation held: The practice and rhetoric of the Pajama experiment," paper presented at the ISHPSSB meeting, Leuven, July 1995. The PaJaMo, or PaJaMa, experiment, named for the collaboraton of Pardee, Jacob, and Monod, provided early evidence for the role of messenger RNA in protein synthesis. For Pardee's view of Monod and Jacob's appropriation of his sabbatical work, see "The Pajama experiment," in Lwoff and Ullman, eds. (ref. 1), 109-116.
25. Jean-Paul Gaudillière, "How biochemical regulation held: The practice and rhetoric of the Pajama experiment," paper presented at the ISHPSSB meeting, Leuven, July 1995. The PaJaMo, or PaJaMa, experiment, named for the collaboraton of Pardee, Jacob, and Monod, provided early evidence for the role of messenger RNA in protein synthesis. For Pardee's view of Monod and Jacob's appropriation of his sabbatical work, see "The Pajama experiment," in Lwoff and Ullman, eds. (ref. 1), 109-116.
26. The only reference to this work was in a letter written by Pardee on 2 Sep 1959: "In the laboratory, the work is going along quite well. We have brought the repressible carbamyl aspartate transferase to a high degree of purity. . . .We are studying feedback kinetics with the pure enzyme now." Fonds Monod, Archives de l'Institut Pasteur.
27. John Gerhart, interview, Berkeley, June 1992. M. Rachmeler, J. Gerhart, and J. Rosner, "Limited thymidine uptake in E. coli due to an inducible thymidine phosphorylase," Biochimica et Biophysica Acta, 49 (1961), 222-225.
28. Jean-Pierre Changeux, interview, Pasteur Institute, 25 Aug 1992.
29. The trend towards the focus of research efforts on cell regulation is well-represented by two prominent meetings in the mid-1950s. See Enzymes: Units of biological structure and function, Henry Ford Hospital International Symposium, ed. Oliver H. Gaebler (New York, 1956) and Ciba Foundation Symposium on the Regulation of Cell Metabolism, eds. G.E.W. Wolstenholme and Cecilia M. O'Connor (London, 1959). On use of co-citation data, etc., to establish scientific networks, Nicholas Mullins, "The development of a scientific specialty: The phage group and the origins of molecular biology," Minerva, 10 (1976), 51-82.
30. The trend towards the focus of research efforts on cell regulation is well-represented by two prominent meetings in the mid-1950s. See Enzymes: Units of biological structure and function, Henry Ford Hospital International Symposium, ed. Oliver H. Gaebler (New York, 1956) and Ciba Foundation Symposium on the Regulation of Cell Metabolism, eds. G.E.W. Wolstenholme and Cecilia M. O'Connor (London, 1959). On use of co-citation data, etc., to establish scientific networks, Nicholas Mullins, "The development of a scientific specialty: The phage group and the origins of molecular biology," Minerva, 10 (1976), 51-82.
31. The trend towards the focus of research efforts on cell regulation is well-represented by two prominent meetings in the mid-1950s. See Enzymes: Units of biological structure and function, Henry Ford Hospital International Symposium, ed. Oliver H. Gaebler (New York, 1956) and Ciba Foundation Symposium on the Regulation of Cell Metabolism, eds. G.E.W. Wolstenholme and Cecilia M. O'Connor (London, 1959). On use of co-citation data, etc., to establish scientific networks, Nicholas Mullins, "The development of a scientific specialty: The phage group and the origins of molecular biology," Minerva, 10 (1976), 51-82.
32. Leo Szilard's list of laboratories to visit in 1959 is among Monod's papers, Archives de l'Institut Pasteur.
33. Davis to Monod, 1 Oct 1957, Fonds Monod, Archives de l'Institut Pasteur.
34. On the biochemical uses of isotopes: Robert E. Kohler, "Robert Schoenheimer, Isotopic tracers, and biochemistry in the 1930s," HSPS, 8 (1977), 257-298. On Beadle and Tatum's innovative use of mutants to trace metabolic pathways: Lily E. Kay, "Selling pure science in wartime: The biochemical genetics of G.W. Beadle," JHB, 22 (1989), 73-101, and Kohler (ref. 6).
35. On the biochemical uses of isotopes: Robert E. Kohler, "Robert Schoenheimer, Isotopic tracers, and biochemistry in the 1930s," HSPS, 8 (1977), 257-298. On Beadle and Tatum's innovative use of mutants to trace metabolic pathways: Lily E. Kay, "Selling pure science in wartime: The biochemical genetics of G.W. Beadle," JHB, 22 (1989), 73-101, and Kohler (ref. 6).
36. For the contribution of the phage group to molecular biology, see Michel Morange, Histoire de la biologie moléculaire (Paris, 1994). Recollections of the phage group members are collected in John Cairns, Gunther S. Stent, and James D. Watson, eds., Phage and the origins of molecular biology (Cold Spring Harbor, NY, 1966). F.L. Holmes has pointed to the interest in regulation among other and earlier biochemists ("The life cycles: The regulation of intermediary metabolism," unpublished mss.). He includes metabolic biochemists working on mammalian systems such as Hans Krebs and Carl and Gerty Cori, whereas the network we discuss worked with microbes, for which genetic methods were newly available.
37. For the contribution of the phage group to molecular biology, see Michel Morange, Histoire de la biologie moléculaire (Paris, 1994). Recollections of the phage group members are collected in John Cairns, Gunther S. Stent, and James D. Watson, eds., Phage and the origins of molecular biology (Cold Spring Harbor, NY, 1966). F.L. Holmes has pointed to the interest in regulation among other and earlier biochemists ("The life cycles: The regulation of intermediary metabolism," unpublished mss.). He includes metabolic biochemists working on mammalian systems such as Hans Krebs and Carl and Gerty Cori, whereas the network we discuss worked with microbes, for which genetic methods were newly available.
38. The researchers usually credited for initially drawing attention to this type of regulation (some scientists dispute the priority) are Aaron Novick and Leo Szilard ("Experiments with the chemostat on the rates of amino acid synthesis in bacteria," Dynamics of growth processes (Princeton, 1954), 21-32), and Philip Abelson and coworkers at Carnegie Institute (R.B. Roberts, D.B. Cowie, P.H. Abelson, E.T. Bolton, and R.J. Britten, "Studies of biosynthesis in Escherichia coli," Carnegie Institution of Washington, publication 607, 1955).
39. The researchers usually credited for initially drawing attention to this type of regulation (some scientists dispute the priority) are Aaron Novick and Leo Szilard ("Experiments with the chemostat on the rates of amino acid synthesis in bacteria," Dynamics of growth processes (Princeton, 1954), 21-32), and Philip Abelson and coworkers at Carnegie Institute (R.B. Roberts, D.B. Cowie, P.H. Abelson, E.T. Bolton, and R.J. Britten, "Studies of biosynthesis in Escherichia coli," Carnegie Institution of Washington, publication 607, 1955).
40. H.E. Umbarger. "Evidence for a negative-feedback mechanism in the biosynthesis of isoleucine," Science, 123 (1956), 848. One year later, Umbarger generalized his new mechanism into the biological norm, arguing that the logic of negative feedback itself could be used as a tool to map metabolic pathways: he argued that since valine inhibited the enzyme using acetate and lactate to make aceto-lactate then this enzyme must be the first one in the pathway leading to valine. H.E. Umbarger, B. Brown, E.J. Eyring. "Acetolactate, an early intermediate in valine biosynthesis." Journal of the American Chemical Society, 79 (1957), 2980-2981.
41. H.E. Umbarger. "Evidence for a negative-feedback mechanism in the biosynthesis of isoleucine," Science, 123 (1956), 848. One year later, Umbarger generalized his new mechanism into the biological norm, arguing that the logic of negative feedback itself could be used as a tool to map metabolic pathways: he argued that since valine inhibited the enzyme using acetate and lactate to make aceto-lactate then this enzyme must be the first one in the pathway leading to valine. H.E. Umbarger, B. Brown, E.J. Eyring. "Acetolactate, an early intermediate in valine biosynthesis." Journal of the American Chemical Society, 79 (1957), 2980-2981.
42. Richard A. Yates and Arthur B. Pardee, "Control of pyrimidine biosynthesis in Escherichia coli by a feed-back mechanism," JBC, 221 (1956), 757-770.
43. This view is articulated by Bernard D. Davis in his historical overview of the field of cell regulation in the introduction to the Cold Spring Harbor volume, "Cellular regulatory mechanisms," CSHSQB, 26 (1961), 1-10.
44. Boris Magasanik pointed out to the authors that the "sparing" effect was commonly recognized among the Harvard bacteriologists, but only Umbarger perceived the biochemical contradiction of this notion (i.e., how could one amino acid inhibit synthesis of an unrelated amino acid?) and invented "negative feedback" to account for it. Interview with Boris Magasanik, May 1993.
45. Norbert Wiener, Cybernetics: Or control and communication in the animal and the machine (Cambridge, 1948, 1961). On the traffic between the physical sciences and life sciences in the formation and uses of "cyberscience," see Evelyn Fox Keller, "The body of a new machine: Situating the organism between telegraphs and computers," Perspectives on science, 2 (1994), 302-323. For the role played by information theory and cybernetics in work on the genetic code, see Lily E. Kay, "Who wrote the book of life? Information and the transformation of molecular biology, 1945-55," Science in context, 8 (1995), 609-34.
46. Norbert Wiener, Cybernetics: Or control and communication in the animal and the machine (Cambridge, 1948, 1961). On the traffic between the physical sciences and life sciences in the formation and uses of "cyberscience," see Evelyn Fox Keller, "The body of a new machine: Situating the organism between telegraphs and computers," Perspectives on science, 2 (1994), 302-323. For the role played by information theory and cybernetics in work on the genetic code, see Lily E. Kay, "Who wrote the book of life? Information and the transformation of molecular biology, 1945-55," Science in context, 8 (1995), 609-34.
47. Norbert Wiener, Cybernetics: Or control and communication in the animal and the machine (Cambridge, 1948, 1961). On the traffic between the physical sciences and life sciences in the formation and uses of "cyberscience," see Evelyn Fox Keller, "The body of a new machine: Situating the organism between telegraphs and computers," Perspectives on science, 2 (1994), 302-323. For the role played by information theory and cybernetics in work on the genetic code, see Lily E. Kay, "Who wrote the book of life? Information and the transformation of molecular biology, 1945-55," Science in context, 8 (1995), 609-34.
48. Sir Hans Krebs, "Chairman's introductory address: Rate-limiting factors in cell respiration," Ciba Foundation (ref. 15), 2.
49. For example, in Luigi Gorini's article of 1958, "Regulation en retour (feedback control) de la synthèse de l'arginine chez Escherichia coli," the mode of action could be mediated through genes, enzymes, or both. L. Gorini, BSCB, 40 (1958), 1939.
50. Even Umbarger used feedback for both enzyme synthesis and activity; Umbarger and Barbara Brown, "Isoleucine and valine metabolism in Escherichia coli, VII. A negative feedback mechanism controlling isoleucine biosynthesis," Journal of bacteriology, 233 (1958), 415-420.
51. Arthur Pardee, "Mechanisms for control of enzyme synthesis and enzyme activity in bacteria," Ciba Foundation (ref. 15), 295-304, on 298.
52. On the development of protein synthesis research at the Pasteur from enzyme adaptation studies, see Jean-Paul Gaudillière, "J. Monod, S. Spiegelman et l'adaptation enzymatique. Programmes de recherche, cultures locales et traditions disciplinaires." History and philosophy of the life sciences, 14 (1992), 23-71.
53. Foreign visitors in Monod's laboratory have been listed by Madeleine Brunerie, Archives de l'Institut Pasteur. On "obligatory passage points," see Bruno Latour, "Give me a laboratory and I will raise the world," in Karin D. Knorr-Cetina and Michael Mulkay, eds., Science observed: Perspectives on the social study of science (Beverly Hills, 1983), 141-170, and Science in action (Cambridge, 1987). On the international dimension of molecular biology see Pnina G. Abir-Am, "From multi-disciplinary collaboration to transnational objectivity: International space as constitutive of molecular biology," in E. Crawford, T. Shinn, and S. Sorlin, eds., Denationalizing science: The contexts of international scientific practice (Dordrecht, 1992-93), 153-186.
54. Foreign visitors in Monod's laboratory have been listed by Madeleine Brunerie, Archives de l'Institut Pasteur. On "obligatory passage points," see Bruno Latour, "Give me a laboratory and I will raise the world," in Karin D. Knorr-Cetina and Michael Mulkay, eds., Science observed: Perspectives on the social study of science (Beverly Hills, 1983), 141-170, and Science in action (Cambridge, 1987). On the international dimension of molecular biology see Pnina G. Abir-Am, "From multi-disciplinary collaboration to transnational objectivity: International space as constitutive of molecular biology," in E. Crawford, T. Shinn, and S. Sorlin, eds., Denationalizing science: The contexts of international scientific practice (Dordrecht, 1992-93), 153-186.
55. Foreign visitors in Monod's laboratory have been listed by Madeleine Brunerie, Archives de l'Institut Pasteur. On "obligatory passage points," see Bruno Latour, "Give me a laboratory and I will raise the world," in Karin D. Knorr-Cetina and Michael Mulkay, eds., Science observed: Perspectives on the social study of science (Beverly Hills, 1983), 141-170, and Science in action (Cambridge, 1987). On the international dimension of molecular biology see Pnina G. Abir-Am, "From multi-disciplinary collaboration to transnational objectivity: International space as constitutive of molecular biology," in E. Crawford, T. Shinn, and S. Sorlin, eds., Denationalizing science: The contexts of international scientific practice (Dordrecht, 1992-93), 153-186.
56. See Richard M. Burian, Jean Gayon, and Doris Zallen, "The singular fate of genetics in the history of French biology, 1900-1940," JHB, 21 (1988), 357-402; Richard M. Burian and Jean Gayon, "Un évolutionniste bernardien à l'Institut Pasteur? Morphologie des ciliés et évolution physiologique dans l'oevre d'André Lwoff," in Michel Morange, ed., L'Institut Pasteur (Paris, 1991), 165-185; and Jean-Paul Gaudillière, "Molecular biology in the French tradition? Redefining local traditions and disciplinary patterns,' JHB, 26 (1993), 473-498.
57. See Richard M. Burian, Jean Gayon, and Doris Zallen, "The singular fate of genetics in the history of French biology, 1900-1940," JHB, 21 (1988), 357-402; Richard M. Burian and Jean Gayon, "Un évolutionniste bernardien à l'Institut Pasteur? Morphologie des ciliés et évolution physiologique dans l'oevre d'André Lwoff," in Michel Morange, ed., L'Institut Pasteur (Paris, 1991), 165-185; and Jean-Paul Gaudillière, "Molecular biology in the French tradition? Redefining local traditions and disciplinary patterns,' JHB, 26 (1993), 473-498.
58. See Richard M. Burian, Jean Gayon, and Doris Zallen, "The singular fate of genetics in the history of French biology, 1900-1940," JHB, 21 (1988), 357-402; Richard M. Burian and Jean Gayon, "Un évolutionniste bernardien à l'Institut Pasteur? Morphologie des ciliés et évolution physiologique dans l'oevre d'André Lwoff," in Michel Morange, ed., L'Institut Pasteur (Paris, 1991), 165-185; and Jean-Paul Gaudillière, "Molecular biology in the French tradition? Redefining local traditions and disciplinary patterns,' JHB, 26 (1993), 473-498.
59. Henning Karström, Über die Enzymbildung in Bakterien und über einige physiologische Eigenschaften der untersuchten Bakterienarten (Helsinki, 1930). Karström was the first to distinguish between constitutive and adaptive enzymes, but he followed work on adaptation in yeast by F. Dienert (c. 1900). See Thomas D. Brock, The emergence of bacterial genetics (Cold Spring Harbor, New York, 1990), 267 ff.
60. Henning Karström, Über die Enzymbildung in Bakterien und über einige physiologische Eigenschaften der untersuchten Bakterienarten (Helsinki, 1930). Karström was the first to distinguish between constitutive and adaptive enzymes, but he followed work on adaptation in yeast by F. Dienert (c. 1900). See Thomas D. Brock, The emergence of bacterial genetics (Cold Spring Harbor, New York, 1990), 267 ff.
61. Gaudillière (ref. 30).
62. On the decline of Pz's status see Gaudillière (ref. 30).
63. For aspects of this transition see Judson (ref. 1).
64. Jean-François Picard. La République des Savants: la Recherche Française et le CNRS (Paris, 1990).
65. Robert Gilpin, La science et l'Etat en France (Paris, 1970).
66. Pierre Piganiol and Louis Villecourt, Pour une politique scientifique (Paris, 1963).
67. Jean-Paul Gaudillière, "Chimie biologique ou biologie moléculaire: La biochimie au CNRS dans les années soixante," Cahiers pour l'Histoire du CNRS, 7 (1990), 91-147.
68. Jean-Pierre Changeux, "A Ph.D. with Jacques Monod: Prehistory of allosteric proteins," in Lwoff and Ullman, eds. (ref. 1), 194. Changeux recently published new recollections based on documents not consulted before. Insofar as dates and factual circumstances are concerned, his new testimony agrees with our other sources and with the account we have constructed from them. Recollections and interpretations, however, have been altered by the course of discussions with other actors, including historians of molecular biology such as ourselves. As Changeux rightly put it: "to reconstruct the genesis of concepts which took place about thirty years ago, hinges upon the recollection of now hardly conscious events, or even of ideas, dialogues and reasonings that were subsequently recreated, repelled to the unconscious or simply forgotten." Jean-Pierre Changeux, "Allosteric proteins: From regulatory enzymes to receptors; Personal recollections," BioEssays, 15 (1993), 625-634, quote on 625.
69. Jean-Pierre Changeux, "A Ph.D. with Jacques Monod: Prehistory of allosteric proteins," in Lwoff and Ullman, eds. (ref. 1), 194. Changeux recently published new recollections based on documents not consulted before. Insofar as dates and factual circumstances are concerned, his new testimony agrees with our other sources and with the account we have constructed from them. Recollections and interpretations, however, have been altered by the course of discussions with other actors, including historians of molecular biology such as ourselves. As Changeux rightly put it: "to reconstruct the genesis of concepts which took place about thirty years ago, hinges upon the recollection of now hardly conscious events, or even of ideas, dialogues and reasonings that were subsequently recreated, repelled to the unconscious or simply forgotten." Jean-Pierre Changeux, "Allosteric proteins: From regulatory enzymes to receptors; Personal recollections," BioEssays, 15 (1993), 625-634, quote on 625.
70. Monod visited Harvard Medical School on his way to the meeting on enzymes which took place at the Henry Ford Hospital in Detroit, 1-3 Nov 1955, mentioned in ref. 15, the proceedings of which are cited. Thus, as Umbarger points out, "Monod may have been the only person in the world who knew of our [his and Pardee's] independent and essentially simultaneous discoveries." Quote from H.E. Umbarger, "The origin of a useful concept - Feedback inhibition," Protein science, 1 (1992), 1392-1395, on 1394.
71. Monod to Umbarger, 16 June 1959, Fonds Monod, Archives de l'Institut Pasteur.
72. Changeux interview, 25 Aug 1992; Jean-Pierre Changeux, Cahiers, Volume III.
73. On 24 June 1959, Monod wrote to Pardee: "I wonder if there any news or recent experiments. . .I want to include a discussion on feedback inhibition to clarify the differences between feedback inhibition and repression. If you have data along these lines, I would be interested to have them: for instance further studies on carbamyl-transferase." Fonds Monod, Archives de l'Institut Pasteur.
74. Jean-Pierre Changeux, Cahiers, Vol. I (henceforth as Cahier I), 20-25. Changeux allowed us to copy three early laboratory notebooks which he still possesses. Most of the notebooks from his graduate work have not survived.
75. Changeux, Cahier I, 30 and following.
76. Changeux, Cahier I, 32-33.
77. Changeux, Cahier III, 43-44. No date, presumably late 1959.
78. Changeux, 1993 (ref. 41), 626.
79. Changeux has expressed the frustrations he felt conducting his project in isolation: "It was very difficult technically because I had no experience and there was some tradition of [enzyme] biochemistry in the lab but not that much." Interview, 25 Aug 1992, Institut Pasteur, Paris.
80. Changeux, Cahier I, 88-99. This does not mean that everything went well. For instance on 5 Jan, measurements were impossible because the color was unstable.
81. Changeux, Cahier I, 99. The same wording suggests that "deregulation" was then viewed as an alteration of the enzyme structure which may be analogous to aging or denaturation.
82. See Umbarger and Brown (ref. 28).
83. Changeux, Cahier II, 18.
84. Ibid., 30-45.
85. Ibid., 57.
86. Ibid., 57-76.
87. Ibid., 77.
88. Ibid., 84.
89. Ibid., 89.
90. Ibid., 82.
91. Changeux, 1993 (ref. 41), 627. "First attempts to purify the enzyme also resulted in a significant modification of its regulatory properties. . .I tried replacing the 'aging' of the enzyme by heat treatment. In high ionic strength buffer the enzyme was stable up to 55°C: however, 10 minutes under these conditions led to complete loss of sensitivity to L-isoleucine without loss of enzymatic activity."
92. Jean-Paul Changeux. "The feedback control mechanism of biosynthetic L-threonine deaminase by L-isoleucine," CSHSQB, 26 (1961), 313-318, on 314-315.
93. Changeux, 1993 (ref. 40), 627.
94. Changeux (ref. 64), 317.
95. Changeux, 1993 (ref. 41), 627.
96. Interview with John Gerhart, 12 June 1992, Berkeley, CA.
97. Although we discuss Changeux's observation first, this does not mean we wish to reassess priority claims. There is no reason to question that Changeux's and Gerhart's observations were independent and took place during the same time period. We had access to Changeux's notebook from his preliminary project on acetolactate synthetase as well as his early results with threonine deaminase and for narrative purposes analyzed them first.
98. Letter from Jacques Monod to Roger Stanier, 18 Feb 1958, Fonds Monod, Archives de l'Institut Pasteur.
99. Howard Schachman, 1977, as quoted in Horace Judson, The eighth day of creation (ref. 1), 404; interview with Howard Schachman, June 15, 1992, Berkeley, CA.
100. On Stanley's crystallization of TMV in 1935, Lily E. Kay, "W. M. Stanley's crystallization of the tobacco mosaic virus," Isis, 77 (1986), 450-472. On the relevant postwar disciplinary and institutional developments at Berkeley, Angela N.H. Creager, "Wendell Stanley and the dream of a free-standing Department of Biochemistry at U.C. Berkeley," JHB, 29 (1996), 331-360.
101. On Stanley's crystallization of TMV in 1935, Lily E. Kay, "W. M. Stanley's crystallization of the tobacco mosaic virus," Isis, 77 (1986), 450-472. On the relevant postwar disciplinary and institutional developments at Berkeley, Angela N.H. Creager, "Wendell Stanley and the dream of a free-standing Department of Biochemistry at U.C. Berkeley," JHB, 29 (1996), 331-360.
102. H.K. Schachman, A.B. Pardee, and R.Y. Stanier, "Studies on the macromolecular organization of microbial cells," Archives of biochemistry and biophysics, 38 (1952), 245-260. They went on in a further experiment with photosynthetic cells to demonstrate that chloroplasts are found in a discrete cellular organelle, the chromatophore. Pardee, Schachman, and Stanier, "Chromatophores of Rhodospirillum rubrum," Nature, 169 (1952), 282-284.
103. H.K. Schachman, A.B. Pardee, and R.Y. Stanier, "Studies on the macromolecular organization of microbial cells," Archives of biochemistry and biophysics, 38 (1952), 245-260. They went on in a further experiment with photosynthetic cells to demonstrate that chloroplasts are found in a discrete cellular organelle, the chromatophore. Pardee, Schachman, and Stanier, "Chromatophores of Rhodospirillum rubrum," Nature, 169 (1952), 282-284.
104. Pardee was one of the authors who proposed the name change from "adaptation" to "induction." J. Monod, M. Cohn, M.R. Pollock, S. Spiegelman, and R.Y. Stanier, "Terminology of enzyme formation," Nature, 172 (1953), 1096.
105. The opening sentence of "Pyrimidine biosynthesis in Escherichia coli" by Richard A. Yates and Pardee, JBC, 221 (1956), 743-56. Pardee had other laboratory members working on other metabolic pathways, e.g., E. H. Wormser and Pardee, "Regulation of threonine biosynthesis in E. coli," Archives of biochemistry and biophysics, 78 (1958), 416-432.
106. The opening sentence of "Pyrimidine biosynthesis in Escherichia coli" by Richard A. Yates and Pardee, JBC, 221 (1956), 743-56. Pardee had other laboratory members working on other metabolic pathways, e.g., E. H. Wormser and Pardee, "Regulation of threonine biosynthesis in E. coli," Archives of biochemistry and biophysics, 78 (1958), 416-432.
107. Yates and Pardee (ref. 22).
108. An exchange between Pardee and Fritz Lipmann in 1958 about Yates' results confirms that Pardee believed cytidine regulated enzyme activity by binding at the active site. Ciba Foundation Symposium (ref. 15), 309-310).
109. Yates and Pardee, "Control by uracil of formation of enzymes required for orotate synthesis," JBC, 227 (1957), 677-692.
110. E.g., M. Riley, A.B. Pardee, F. Jacob, and J. Monod, "On the expression of a structural gene," JMB, 2 (1960), 216-225; A.C. Willson and A.B. Pardee, "Regulation of flavin synthesis by E. coli," Journal of general microbiology, 28 (1962), 283-303.
111. E.g., M. Riley, A.B. Pardee, F. Jacob, and J. Monod, "On the expression of a structural gene," JMB, 2 (1960), 216-225; A.C. Willson and A.B. Pardee, "Regulation of flavin synthesis by E. coli," Journal of general microbiology, 28 (1962), 283-303.
112. Margaret Shepherdson and Pardee, "Production and crystallization of aspartate transcarbamylase," JBC, 235 (1960), 3233-3237.
113. Interview with John Gerhart, 12 June 1992, Berkeley, CA.
114. John Gerhart, Notebook, 23 Sep 1960. Gerhart allowed us to copy this early laboratory notebook which he still possesses from his graduate work.
115. Gerhart, Notebook, 23 Sep 1960.
116. Gerhart, Notebook, 26 Sep 1960.
117. Ibid.
118. Gerhart, Notebook, 12 Oct 1960.
119. Gerhart, Notebook, 7 Dec 1960.
120. Gerhart, Notebook, 15 Dec 1960.
121. Gerhart, Notebook, 20 Dec 1960.
122. Gerhart, personal communication, 19 Oct 1995.
123. Gerhart, Notebook, "Notes" following experiment, 20 Dec 1960.
124. Gerhart and Pardee, "Separation of feedback inhibition from activity of aspartate transcarbamylase (ATCase)," Fed. Proc., 20 (1961), 224.
125. Gerhart, Notebook, 22 Mar 1961, and interview with Gerhart, 12 June 1992, Berkeley.
126. Interview with Gerhart, 12 June 1992, Berkeley. On Reichard, interview with Arthur B. Pardee in Boston, 4 June 1992; Pardee to author, October 3, 1995.
127. Gerhart, Notebook, 24 Mar 1961.
128. Gerhart, Notebook, "List of ATCase Inhibitors," Mar 1961.
129. Gerhart, Notebook, 30 Mar 1961.
130. Gerhart, Notebook, 4 Apr 1961.
131. Gerhart, Notebook, 10 May 1961.
132. J.P. Changeux, "Effet des Analogues de la L-thréonine et de la L-isoleucine sur la L-Thréonine Désaminase." JMB, 4 (1962), 220-225.
133. Changeux, "Allosteric interactions on biosynthetic L-threonine deaminase from E. coli K12." CSHSQB, 28 (1963), 497-504. Also see Changeux (ref. 41), 1993, 628.
134. Gerhart and Pardee, "The enzymology of control by feedback inhibition," JBC, 237 (Mar 1962), 891-896.
135. Interview with Pardee, 4 June 1992, Boston. The most extensive comments on the unusual sigmoidal kinetics of ATCase are relegated to a footnote, "Further kinetic studies and possible explanations for their anomalous appearance may be found in the thesis of J.C. Gerhart, University of California, 1962." Gerhart and Pardee (ref. 102), 893.
136. Gerhart and Pardee (ref. 102), 895.
137. Pardee has argued that Monod's visit to Berkeley in the spring of 1961, at which time Pardee told him of their developing two site model, might have led to a conscious recasting of Changeux's desensitization results. (Letter to the author, 3 Oct 1995.) We do not wish to enter the priority dispute between the two laboratories, but clearly communications between the two laboratories shaped the research paths and the public presentations. Monod and Jacob leaned heavily on the corroboration of Gerhart and Pardee's experiments in generalizing Changeux's results into "allosteric inhibition," as discussed below.
138. Gerhart traces the argument and the two site theory back to discussions between Umbarger and Pardee sometime in the spring 1960, as quoted at the beginning of section 3. Interview with Gerhart (ref. 68). Gerhart's focus on kinetics of ATCase in March 1960 fits most closely with this recollection.
139. Gerhart and Pardee (ref. 102), 893.
140. This difference has been underlined by Changeux. Commenting on Gerhart and Pardee's paper, he wrote: "They also reached the conclusion that the enzyme has a second site, distinct from the active site, for which the end product has high affinity. Yet, they did not attempt to generalize their conclusions beyond feedback inhibition of regulator enzymes." Changeux, 1993 (ref. 41), 628. Gerhart and Pardee (ref. 102), 892.
141. Gerhart and Pardee (ref. 102), 895-896.
142. John Gerhart, The enzymology of feedback inhibition (Ph.D. dissertation, University of California, Berkeley, 1962).
143. On the history of the meetings and their significance to the development of molecular biology, Nathaniel C. Comfort, "Arc of a paradigm, The Cold Spring Harbor Symposium on Quantitative Biology, 1933-1953," presented to the Joint Atlantic Seminar in the History of Biology, 25 Mar 1995, Cold Spring Harbor, NY.
144. Jacques Monod and François Jacob, "General conclusions: Teleonomic mechanisms in cellular metabolism, growth, and differentiation," CSHSQB, 26, 389-401. Their paper on the operon model was "On the regulation of gene activity," 193-212.
145. Ibid., 391.
146. Ibid.
147. Among Monod's unpublished manuscripts in the Archives de l'Institut Pasteur is an unfinished monograph entitled "Cybernétique enzymatique," which his secretary, Madeleine Brunerie dates to 1958 or 1959. He was primarily interested in explaining enzyme adaptation in terms of cybernetics.
148. This challenge to Umbarger's claim of discovering feedback inhibition by citing the earlier work of Novick and Szilard served Monod's interest, due both to his long-standing relationship with Szilard (who was an honorary "Pastorian") and the fact that Novick and Szilard's experiments relied on the use of Monod's instrument, the chemostat. Novick and Szilard (ref. 20).
149. Umbarger, "Discussion" (ref. 23), 401. Umbarger was promoting the use of "endproduct inhibition" as a more precise alternative to feedback inhibition.
150. In the conclusions from Cold Spring Harbor in 1961, Monod and Jacob write, "Studies of the structure of the two sites and of their interaction, using analogues of the substrate and inhibitor, might conceivably lead to interpretations in terms of the 'induced-fit' theory of Koshland (1959)" (ref. 112), 391. This coupling of substrates and analogues draws strongly on Monod's model of β-galactosidase. The reference is to D.E. Koshland, Jr., "Enzyme flexibility and enzyme action," JCCP, 54 (1959), 245-258. Monod's paper of 1963, "Allosteric proteins and cellular control systems" (see footnote 126), contains three references to papers by Daniel Koshland regarding induced fit and enzyme action. The citations are "Application of a theory of enzyme specificity to protein synthesis," National Academy of Science, Proceedings, 44 (1958), 98-104; "The active site and enzyme action," Advances in enzymology, 22 (1960), 45-97; and "Catalysis in life and in the test tube," Horizons in biochemistry (New York, 1962), 265.
151. In the conclusions from Cold Spring Harbor in 1961, Monod and Jacob write, "Studies of the structure of the two sites and of their interaction, using analogues of the substrate and inhibitor, might conceivably lead to interpretations in terms of the 'induced-fit' theory of Koshland (1959)" (ref. 112), 391. This coupling of substrates and analogues draws strongly on Monod's model of β-galactosidase. The reference is to D.E. Koshland, Jr., "Enzyme flexibility and enzyme action," JCCP, 54 (1959), 245-258. Monod's paper of 1963, "Allosteric proteins and cellular control systems" (see footnote 126), contains three references to papers by Daniel Koshland regarding induced fit and enzyme action. The citations are "Application of a theory of enzyme specificity to protein synthesis," National Academy of Science, Proceedings, 44 (1958), 98-104; "The active site and enzyme action," Advances in enzymology, 22 (1960), 45-97; and "Catalysis in life and in the test tube," Horizons in biochemistry (New York, 1962), 265.
152. In the conclusions from Cold Spring Harbor in 1961, Monod and Jacob write, "Studies of the structure of the two sites and of their interaction, using analogues of the substrate and inhibitor, might conceivably lead to interpretations in terms of the 'induced-fit' theory of Koshland (1959)" (ref. 112), 391. This coupling of substrates and analogues draws strongly on Monod's model of β-galactosidase. The reference is to D.E. Koshland, Jr.,
153. In the conclusions from Cold Spring Harbor in 1961, Monod and Jacob write, "Studies of the structure of the two sites and of their interaction, using analogues of the substrate and inhibitor, might conceivably lead to interpretations in terms of the 'induced-fit' theory of Koshland (1959)" (ref. 112), 391. This coupling of substrates and analogues draws strongly on Monod's model of β-galactosidase. The reference is to D.E. Koshland, Jr., "Enzyme flexibility and enzyme action," JCCP, 54 (1959), 245-258. Monod's paper of 1963, "Allosteric proteins and cellular control systems" (see footnote 126), contains three references to papers by Daniel Koshland regarding induced fit and enzyme action. The citations are "Application of a theory of enzyme specificity to protein synthesis," National Academy of Science, Proceedings, 44 (1958), 98-104; "The active site and enzyme action," Advances in enzymology, 22 (1960), 45-97; and "Catalysis in life and in the test tube," Horizons in biochemistry (New York, 1962), 265.
154. Monod and Jacob (ref. 112), 396.
155. Ibid., 393.
156. Changeux, 1963 (ref. 101).
157. Interview with Changeux, 25 Aug 1992, Paris. There are no archival sources to help retrieve the process.
158. Monod to Pardee, 8 May 1962, Fonds Monod, Archives de l'Institut Pasteur.
159. Pardee to Monod, 12 May 1962, Fonds Monod, Archives de l'Institut Pasteur.
160. Monod and Jacob (ref. 112).
161. Monod, Changeux and Jacob, "Allosteric proteins and cellular control systems," JMB, 6 (1963), 306-329.
162. Considering the frustrations Monod and Changeux encountered trying to develop a good experimental system, it was a good tactic to write a review article that summarized and reinterpreted the work of others.
163. Monod, Changeux, and Jacob (ref. 126), 306, emphases added.
164. Monod, Changeux, and Jacob were not the first to perceive this similarity. Bernard Davis noted that the sigmoidal kinetics curves Changeux presented in his 1961 Cold Spring Harbor paper resembled those of hemoglobin (ref. 112), 318. Also, John Gerhart speculated in his thesis that the sigmoidal curves for ATCase might be due to substrate cooperative binding, as in hemoglobin. John Gerhart, "Appendix, Possible explanations for the anomalous kinetics of ATCase (ref. 109), 65-70. At the same time, the centrality of hemoglobin in Monod, Jacob, and Changeux's review made their analogy more consequential in the evolution of allostery.
165. Monod, Changeux, and Jacob (ref. 126), 322.
166. Ibid.
167. On the history of physiological research on hemoglobin, see John T. Edsall, "Hemoglobin and the origins of the concept of allosterism," Fed. Proc., 39 (1980), 226-235. On the collaborative efforts of researchers and clinicians concerning the molecular structure of hemoglobin, see Soraya de Chadarevian, "Following molecules: molecular biology and medicine, 1950s-60s" in Molecularising biology and medicine, Soraya de Chadarevian and Harmke Kamminga, eds. (Harvard University Press, forthcoming). For a typical representation of hemoglobin for medical students, see Textbook of physiology and biochemistry by George H. Bell, J. Norman Davidson, and Harold Scarborough (Baltimore, 1959), 563.
168. On the history of physiological research on hemoglobin, see John T. Edsall, "Hemoglobin and the origins of the concept of allosterism," Fed. Proc., 39 (1980), 226-235. On the collaborative efforts of researchers and clinicians concerning the molecular structure of hemoglobin, see Soraya de Chadarevian, "Following molecules: molecular biology and medicine, 1950s-60s" in Molecularising biology and medicine, Soraya de Chadarevian and Harmke Kamminga, eds. (Harvard University Press, forthcoming). For a typical representation of hemoglobin for medical students, see Textbook of physiology and biochemistry by George H. Bell, J. Norman Davidson, and Harold Scarborough (Baltimore, 1959), 563.
169. On the history of physiological research on hemoglobin, see John T. Edsall, "Hemoglobin and the origins of the concept of allosterism," Fed. Proc., 39 (1980), 226-235. On the collaborative efforts of researchers and clinicians concerning the molecular structure of hemoglobin, see Soraya de Chadarevian, "Following molecules: molecular biology and medicine, 1950s-60s" in Molecularising biology and medicine, Soraya de Chadarevian and Harmke Kamminga, eds. (Harvard University Press, forthcoming). For a typical representation of hemoglobin for medical students, see Textbook of physiology and biochemistry by George H. Bell, J. Norman Davidson, and Harold Scarborough (Baltimore, 1959), 563.
170. See Lily E. Kay, The molecular vision of life: Caltech, The Rockefeller Foundation, and the rise of the new biology (New York, 1993), chapt. 5 and epilogue. See also Daniel J. Kevles, "Blood, big science, and biochemistry," in In the name of eugenics: Genetics and the uses of human heredity (Cambridge, MA:, 1985, 1995), chapt 15.
171. See Lily E. Kay, The molecular vision of life: Caltech, The Rockefeller Foundation, and the rise of the new biology (New York, 1993), chapt. 5 and epilogue. See also Daniel J. Kevles, "Blood, big science, and biochemistry," in In the name of eugenics: Genetics and the uses of human heredity (Cambridge, MA:, 1985, 1995), chapt 15.
172. Soraya de Chadarevian, "Sequences, conformation, information: Biochemists and molecular biologists in the 1950s," JHB, 29 (1996), 361-386.
173. M.F. Perutz, M.G. Rossman, Ann F. Cullis, Hilary Muirhead, Georg Will, and C.T. North, "Structure of haemoglobin: A three-dimensional Fourier synthesis at 5.5 Å resolution, obtained by x-ray analysis," Nature, 185 (1960), 416-422; M.F. Perutz, "The hemoglobin molecule," Scientific American, 211 (1963), 64-76.
174. M.F. Perutz, M.G. Rossman, Ann F. Cullis, Hilary Muirhead, Georg Will, and C.T. North, "Structure of haemoglobin: A three-dimensional Fourier synthesis at 5.5 Å resolution, obtained by x-ray analysis," Nature, 185 (1960), 416-422; M.F. Perutz, "The hemoglobin molecule," Scientific American, 211 (1963), 64-76.
175. Jean-Paul Gaudillière, "Biochimistes et biomédecine dans l'après-guerre: Deux itinéraires entre laboratoire et hôpital," Sciences Sociales et Santé, 10 (1992), 107-147; idem., "Molecular biologists, biochemists and messenger RNA: The making of a scientific network," JHB, 29 (1996), 417-445.
176. Jean-Paul Gaudillière, "Biochimistes et biomédecine dans l'après-guerre: Deux itinéraires entre laboratoire et hôpital," Sciences Sociales et Santé, 10 (1992), 107-147; idem., "Molecular biologists, biochemists and messenger RNA: The making of a scientific network," JHB, 29 (1996), 417-445.
177. A transcript of the paper Perutz presented and the discussion which followed can be found in the Archives DGRST, "Comtes-Rendu du Séminaire de Biologie Moléculaire, by Max Perutz, Structure of Proteins, 18 Mai 1962."
178. M.F. Perutz et al. (ref. 135), 421.
179. H. Muirhead, M.F. Perutz, "Structure of human reduced hemoglobin," CSHSQB, 28 (1963), 455.
180. Jean-Pierre Changeux, interview, Paris, 25 Aug 1993; see also Changeux, 1993 (ref. 41). The significance of Perutz's presentation of his results with hemoglobin should not be underestimated, despite our relatively brief treatment of the event here.
181. Monod, Changeux, and Jacob (ref. 126), 322.
182. 2, and 2,3-diphosphoglycerate," British medical bulletin, 32 (1976), 209-212.
183. Horace Judson recounts, "To be sure, hemoglobin was an unusual allosteric protein in one way: the theory called for separate reactive and regulatory sites, a requirement hemoglobin met by having each if its four sites serve the two distinct functions - reacting locally with oxygen and regulating at a distance the reactivity of the other sites" (Italics added; The eighth day of creation (ref. 1), 603.) To claim that cooperativity of oxygen binding in hemoglobin qualified it as allosteric is paradoxical with respect to the etymology of allo-steric (as other shape), interaction between molecules that are chemically different from one another. It was precisely this disjunction in meanings that necessitated a redefinition of allostery according to the model of hemoglobin. Using Monod's terminology, hemoglobin had homotropic, not heterotropic, effects, and heterotropic effects initially defined allostery.
184. For example, the discussion in Gerhart's thesis of 1962 focuses on the similarity of the Bohr effect in hemoglobin to feedback inhibition (ref. 110), 55-58.
185. Gerhart and Pardee, "The effect of the feedback inhibitor, CTP, on subunit interactions in aspartate transcarbamoylase" CSHSQB, 28 (1963), 491-496. A section of the Cold Spring Harbor meeting in 1963, entitled "Synthesis and structure of macromolecules," was devoted to "Allosteric interactions betwen proteins and small molecules." Gerhart and Pardee, "Aspartate transcarbamylase, an enzyme designed for feedback inhibition," Fed. Proc., 23
186. Gerhart and Pardee, "The effect of the feedback inhibitor, CTP, on subunit interactions in aspartate transcarbamoylase" CSHSQB, 28 (1963), 491-496. A section of the Cold Spring Harbor meeting in 1963, entitled "Synthesis and structure of macromolecules," was devoted to "Allosteric interactions betwen proteins and small molecules." Gerhart and Pardee, "Aspartate transcarbamylase, an enzyme designed for feedback inhibition," Fed. Proc., 23
187. Regarding when and how the collaboration developed is personal communication from John Gerhart, 24 Jul 1992.
188. Interview with John Gerhart, 12 June 992, Berkeley, CA.
189. One interesting and mildly notorious example of this approach was the characterization of DNA in 1954 by the nucleic acid chemist Charles Dekker with Schachman. Based on their own ultracentrifugal experiments as well as other existing data on DNA structure, they postulated that DNA was a double helix like that of Watson and Crick except that the strands were interrupted by breaks every several nucleotides. Their "interrupted two-strand model" was later viewed as an artifact of the preparation process for the DNA. Their strict reliance on the ultracentrifuge and their emphasis on empirical research are notable in contrast to Linus Pauling's attempt during the same period to derive the structure of DNA through model building. C.A. Dekker and H.K. Schachman, "On the macromolecular structure of deoxyribonucleic acid: An interrupted two-strand model," National Academy of Sciences, Proceedings, 40 (1954), 894-908.
190. Despite his achievements as a student, the anti-Semitism prevailing even in the U.S. made it difficult for him to get a good engineering job, so he turned to biological research. A similar account of the anti-Semitism which Arthur Kornberg faced as an M.D., and which similarly motivated his move into research, is found in his autobiography, For the love of enzymes: The odyssey of a biochemist (Cambridge, MA, 1989).
191. Interview with Howard Schachman, 15 June 1992, Berkeley, CA.
192. H.K. Schachman, Ultracentrifugation in biochemistry (New York, 1959); ibid., "The ultracentrifuge: Problems and prospects," Biochemistry, 2 (1963), 887-905.
193. H.K. Schachman, Ultracentrifugation in biochemistry (New York, 1959); ibid., "The ultracentrifuge: Problems and prospects," Biochemistry, 2 (1963), 887-905.
194. Schachman, Ultracentrifugation (ref. 151), 1.
195. Gerhart and Schachman, "Distinct subunits for the regulation and catalytic activity of aspartate transcarbamylase," Biochemistry, 4 (1965), 1054-1062.
196. Gerhart and Schachman (ref. 153), 1061-1062.
197. Schachman, Application to the National Science Foundation for a grant in support of Studies on the functional aspects of the quaternary structure of protein, submitted for a grant beginning March 1966, from the Bancroft Library, University of California, Berkeley, CU-151, box 13, folder 20.
198. F.H.C. Crick and L.E. Orgel, "The theory of inter-allelic complementation," JMB, 8 (1964), 161-165. Also see David Perrin, "Complementation between products of β-galactosidase structural gene of Escherichia coli," CSHSQB, 28 (1963), 529-532.
199. F.H.C. Crick and L.E. Orgel, "The theory of inter-allelic complementation," JMB, 8 (1964), 161-165. Also see David Perrin, "Complementation between products of β-galactosidase structural gene of Escherichia coli," CSHSQB, 28 (1963), 529-532.
200. Agnes Ullman, "Being around," in Lwoff and Ullman, eds. (ref. 1), 167.
201. Changeux, 1963 (ref. 101).
202. The results from Changeux's Ph.D. thesis, including these experiments, were published as a series of articles entitled "Sur les propriétés allostériques de la L-thréonine-désaminase," "I. - Méthodes d'étude de la L-thréonine désaminase de biosynthèse," BSCB, 46 (1964), 927-945; "II. - Cinétiques d'action de la L-thréonine désaminase de biosynthèse vis-a-vis du substrat et de l'inhibiteur naturels," BSCB, 46 (1964), 947-961; "III. - Interprétation de l'effet inhibiteur de la L-isoleucine, empêchement stérique or effet allostérique," BSCB, 46 (1964), 1151-1173; "IV - Le phénomène de désensibilisation," BSCB, 47 (1965), 115-139; "V. - La transition allostérique," BSCB, 47 (1965), 267-279; "VI. - Discussion générale," BSCB, 47 (1965), 281-300.
203. The results from Changeux's Ph.D. thesis, including these experiments, were published as a series of articles entitled "Sur les propriétés allostériques de la L-thréonine-désaminase," "I. - Méthodes d'étude de la L-thréonine désaminase de biosynthèse," BSCB, 46 (1964), 927-945; "II. - Cinétiques d'action de la L-thréonine désaminase de biosynthèse vis-a-vis du substrat et de l'inhibiteur naturels," BSCB, 46 (1964), 947-961; "III. - Interprétation de l'effet inhibiteur de la L-isoleucine, empêchement stérique or effet allostérique," BSCB, 46 (1964), 1151-1173; "IV - Le phénomène de désensibilisation," BSCB, 47 (1965), 115-139; "V. - La transition allostérique," BSCB, 47 (1965), 267-279; "VI. - Discussion générale," BSCB, 47 (1965), 281-300.
204. The results from Changeux's Ph.D. thesis, including these experiments, were published as a series of articles entitled "Sur les propriétés allostériques de la L-thréonine-désaminase," "I. - Méthodes d'étude de la L-thréonine désaminase de biosynthèse," BSCB, 46 (1964), 927-945; "II. - Cinétiques d'action de la L-thréonine désaminase de biosynthèse vis-a-vis du substrat et de l'inhibiteur naturels," BSCB, 46 (1964), 947-961; "III. - Interprétation de l'effet inhibiteur de la L-isoleucine, empêchement stérique or effet allostérique," BSCB, 46 (1964), 1151-1173; "IV - Le phénomène de désensibilisation," BSCB, 47 (1965), 115-139; "V. - La transition allostérique," BSCB, 47 (1965), 267-279; "VI. - Discussion générale," BSCB, 47 (1965), 281-300.
205. The results from Changeux's Ph.D. thesis, including these experiments, were published as a series of articles entitled "Sur les propriétés allostériques de la L-thréonine-désaminase," "I. - Méthodes d'étude de la L-thréonine désaminase de biosynthèse," BSCB, 46 (1964), 927-945; "II. - Cinétiques d'action de la L-thréonine désaminase de biosynthèse vis-a-vis du substrat et de l'inhibiteur naturels," BSCB, 46 (1964), 947-961; "III. - Interprétation de l'effet inhibiteur de la L-isoleucine, empêchement stérique or effet allostérique," BSCB, 46 (1964), 1151-1173; "IV - Le phénomène de désensibilisation," BSCB, 47 (1965), 115-139; "V. - La transition allostérique," BSCB, 47 (1965), 267-279; "VI. - Discussion générale," BSCB, 47 (1965), 281-300.
206. The results from Changeux's Ph.D. thesis, including these experiments, were published as a series of articles entitled "Sur les propriétés allostériques de la L-thréonine-désaminase," "I. - Méthodes d'étude de la L-thréonine désaminase de biosynthèse," BSCB, 46 (1964), 927-945; "II. - Cinétiques d'action de la L-thréonine désaminase de biosynthèse vis-a-vis du substrat et de l'inhibiteur naturels," BSCB, 46 (1964), 947-961; "III. - Interprétation de l'effet inhibiteur de la L-isoleucine, empêchement stérique or effet allostérique," BSCB, 46 (1964), 1151-1173; "IV - Le phénomène de désensibilisation," BSCB, 47 (1965), 115-139; "V. - La transition allostérique," BSCB, 47 (1965), 267-279; "VI. - Discussion générale," BSCB, 47 (1965), 281-300.
207. The results from Changeux's Ph.D. thesis, including these experiments, were published as a series of articles entitled "Sur les propriétés allostériques de la L-thréonine-désaminase," "I. - Méthodes d'étude de la L-thréonine désaminase de biosynthèse," BSCB, 46 (1964), 927-945; "II. - Cinétiques d'action de la L-thréonine désaminase de biosynthèse vis-a-vis du substrat et de l'inhibiteur naturels," BSCB, 46 (1964), 947-961; "III. - Interprétation de l'effet inhibiteur de la L-isoleucine, empêchement stérique or effet allostérique," BSCB, 46 (1964), 1151-1173; "IV - Le phénomène de désensibilisation," BSCB, 47 (1965), 115-139; "V. - La transition allostérique," BSCB, 47 (1965), 267-279; "VI. - Discussion générale," BSCB, 47 (1965), 281-300.
208. Robert Baldwin, "Discussions about proteins," in Lwoff and Ullman, eds. (ref. 1), 203.
209. 2 pressure and they have presented convincing evidence that this effect is directly related to the (allosteric) heme-heme interactions in this protein." From the cited article, 88. Monod and coworkers hoped to find that the allosteric activation of phosphorylase b by AMP correlated with the dimerization of the protein, but the results showed otherwise.
210. Jacques Monod, "On the nature of allosteric interactions: A plausible model," undated draft manuscript, Fonds Monod, Archives de l'Institut Pasteur. Monod did publish one early paper on allosteric transitions based primarily on the experiments with threonine deaminase and phosphorylase before he gave up work on these systems. Changeux, Ullmann, and Monod, "Un modèle plausible de la transition allostérique," Colloque International du C.N.R.S., Marseille (1963), 285-295.
211. "Polymer formation; induced fit. The formation of a stable, specific association involving multiple bonds and strict complementarity between protein monomers is likely to imply in most if not all cases a certain amount of rearrangement of the tertiary structure of the monomers (induced fit)." Monod, Unpublished manuscript, ibid., 7.
212. Ibid., 2.
213. Ibid., 9.
214. Although there is no earlier correspondence between Wyman and Monod, there was a previous association. In the 1950s Wyman went to Paris as the scientific attaché of the U.S. Embassy, and became well acquainted with the researchers al the Pasteur Institute, and at this time he and Monod became friends. See Jeffries Wyman, "Recollections of Jacques Monod," in Lwoff and Ullman, eds. (ref. 1), 221-224.
215. Lamprey is a type of primitive fish with a jawless sucking mouth, often mistaken as eel.
216. Wyman to Monod, 10 Jan 1963, Fonds Monod, Archives de l'Institut Pasteur.
217. Monod to Wyman, 24 Apr 1964, Fonds Monod, Archives de l'Institut Pasteur.
218. Monod, "Notes sur les conformations allostériques." Incomplete manuscript, no date, presumably early 1964, Fonds Monod, Archives de l'Institut Pasteur, original in French (translated by the authors).
219. Ibid., 20, original in French (translated by the authors).
220. Monod, Wyman and Changeux, "On the nature of allosteric transitions, a plausible model," JMB, 12 (1965), 88-118. On the historical importance of this paper, see Claude Debru, Philosophie moléculaire: Monod, Wyman, Changeux (Paris, 1987).
221. Monod, Wyman and Changeux, "On the nature of allosteric transitions, a plausible model," JMB, 12 (1965), 88-118. On the historical importance of this paper, see Claude Debru, Philosophie moléculaire: Monod, Wyman, Changeux (Paris, 1987).
222. See Wyman, "Heme proteins," Advances in protein chemistry, 4 (1948), 407-531; "The problem of the heme interactions in hemoglobin and the basis of the Bohr effect," Journal of polymer science, 7 (1951), 499-518; "Allosteric effects in hemoglobin," CSHSQB, 26 (1963), 483-489. For a more comprehensive treatment of Wyman's contributions, Claude Debru, L'esprit des protéines: Histoire et philosophie biochimiques (Paris, 1983), and John T. Edsall, "Jeffries Wyman and myself: A story of two interacting lives," Comprehensive biochemistry, 36 (1985), 99-195, esp. 143-144, 158-167.
223. See Wyman, "Heme proteins," Advances in protein chemistry, 4 (1948), 407-531; "The problem of the heme interactions in hemoglobin and the basis of the Bohr effect," Journal of polymer science, 7 (1951), 499-518; "Allosteric effects in hemoglobin," CSHSQB, 26 (1963), 483-489. For a more comprehensive treatment of Wyman's contributions, Claude Debru, L'esprit des protéines: Histoire et philosophie biochimiques (Paris, 1983), and John T. Edsall, "Jeffries Wyman and myself: A story of two interacting lives," Comprehensive biochemistry, 36 (1985), 99-195, esp. 143-144, 158-167.
224. See Wyman, "Heme proteins," Advances in protein chemistry, 4 (1948), 407-531; "The problem of the heme interactions in hemoglobin and the basis of the Bohr effect," Journal of polymer science, 7 (1951), 499-518; "Allosteric effects in hemoglobin," CSHSQB, 26 (1963), 483-489. For a more comprehensive treatment of Wyman's contributions, Claude Debru, L'esprit des protéines: Histoire et philosophie biochimiques (Paris, 1983), and John T. Edsall, "Jeffries Wyman and myself: A story of two interacting lives," Comprehensive biochemistry, 36 (1985), 99-195, esp. 143-144, 158-167.
225. See Wyman, "Heme proteins," Advances in protein chemistry, 4 (1948), 407-531; "The problem of the heme interactions in hemoglobin and the basis of the Bohr effect," Journal of polymer science, 7 (1951), 499-518; "Allosteric effects in hemoglobin," CSHSQB, 26 (1963), 483-489. For a more comprehensive treatment of Wyman's contributions, Claude Debru, L'esprit des protéines: Histoire et philosophie biochimiques (Paris, 1983), and John T. Edsall, "Jeffries Wyman and myself: A story of two interacting lives," Comprehensive biochemistry, 36 (1985), 99-195, esp. 143-144, 158-167.
226. See Wyman, "Heme proteins," Advances in protein chemistry, 4 (1948), 407-531; "The problem of the heme interactions in hemoglobin and the basis of the Bohr effect," Journal of polymer science, 7 (1951), 499-518; "Allosteric effects in hemoglobin," CSHSQB, 26 (1963), 483-489. For a more comprehensive treatment of Wyman's contributions, Claude Debru, L'esprit des protéines: Histoire et philosophie biochimiques (Paris, 1983), and John T. Edsall, "Jeffries Wyman and myself: A story of two interacting lives," Comprehensive biochemistry, 36 (1985), 99-195, esp. 143-144, 158-167.
227. Monod to Wyman, 3 Sep 1964, Fonds Monod, Archives de l'Institut Pasteur. Translation by authors.
228. Interview with Daniel E. Koshland, Jr., 16 June 1992, Berkeley, CA.
229. D.E. Koshland, Jr., G. Némethy, and D. Filmer, "Comparison of experimental binding data and theoretical models in proteins containing subunits," Biochemistry, 5 (1966), 365-385.
230. Interview with Koshland, 16 June 1992, Berkeley, CA.
231. By 1968 Koshland and coworkers were reporting on the "negative cooperativity" of glyceraldehyde-3-phosphate dehydrogenase, an allosteric effect disallowed by the Monod-Wyman-Changeux model (and one for which the Koshland-Némethy-Filmer model accounts). He was at Brookhaven National Laboratory in the early 1960s, but he was recruited to join the Department of Biochemistry (also Schachman's department) at Berkeley in 1965.
232. Interview with John Gerhart, 12 June 1992, Berkeley, CA.
233. Jean-Pierre Changeux, unpublished letter to the Editor of Nature (20 Apr 1968) (courtesy of the author). His experiments were published in paper jointly authored with Gerhart and Schachman, Changeux, Gerhart, and Schachman, "Allosteric interactions in aspartate transcarbamylase. I. Binding of specific ligands to the native enzyme and its isolated subunits," Biochemistry, 7 (1968), 531-538.
234. Henri Buc, "Mother nature and the design of a regulatory enzyme," in Lwoff and Ullman, eds. (ref. 1), 218. These letters have not survived.
235. Interview with Changeux, Institut Pasteur, 25 Aug 1992. Changeux spoke at length about his frustrations in Berkeley and the differences in laboratory culture compared to Monod's lab at the Institut Pasteur. He found the strong reliance on the analytical ultracentrifuge, an instrument he had no desire to master, particularly disconcerting.
236. Gerhart and Schachman, "Allosteric interactions in aspartate transcarbamylase. II. Evidence for different conformational states of the protein in the presence and absence of specific ligands," Biochemistry, 7(1968), 538-552, on 539.
237. Changeux and Merry M. Rubin, "Interpretation of experimental data in terms of the model of Monod, Wyman, and Changeux," Biochemistry, 7 (1968), 553-561. Rubin and Changeux also wrote a sequel to the Monod-Wymann-Changeux paper, entitled, "On the nature of allosteric transitions: Implications of non-exclusive ligand binding," JMB, 21 (1966), 265-274; cf. ref. 172.
238. Changeux and Merry M. Rubin, "Interpretation of experimental data in terms of the model of Monod, Wyman, and Changeux," Biochemistry, 7 (1968), 553-561. Rubin and Changeux also wrote a sequel to the Monod-Wymann-Changeux paper, entitled, "On the nature of allosteric transitions: Implications of non-exclusive ligand binding," JMB, 21 (1966), 265-274; cf. ref. 172.
239. "The various reaction mixtures contain only unreacted (and undissociated) ATCase, and fully reacted dissociation products of ATCase, rather than a significant amount of partially reacted molecules." Gerhart and Schachman (ref. 183), 541.
240. Schachman (ref. 155), 6.
241. For example, see Lubert Stryer, Biochemistry, 3rd edn. (New York, 1988), 239-242. After presenting the two different models, he invokes ATCase as the exemplary allosteric enzyme. The section titles read: "The concerted model for allosteric interactions" [Monod's model], "The sequential model for allosteric interactions" [Koshland's model], and "The binding of substrates to ATCase leads to a highly concerted allosteric transition" [i.e., it confirms Monod's model].
242. Changeux (ref. 41), 625.
243. Malcolm Dixon and Edwin C. Webb, Enzymes, 2nd edn. (New York, 1964), 522. The first edition to which Changeux referred, was published in 1958.
244. John C. Gerhart, Application for Research Grant to the Department of Health, Education, and Welfare, Public Health Service, renewal of PHS Grant No. CA 07410-03, 15 Mar 1966, 6, courtesy of the author; Howard K. Schachman, "Anatomy and physiology of a regulatory enzyme - aspartate transcarbamylase," Harvey Lectures, 68 (1972), 67-113.
245. Changeux (ref. 41), 632.
246. Changeux, 1974, Contract 67 01.091, Archives de l'Institut Pasteur.
247. Gerhart, Application for Research Grant to the U.S. Department of Health, Education, and Welfare, Public Health Service, 24 May 1963, 6, courtesy of the author.
248. Ibid., 8.
249. Gerhart, PHS renewal grant, 15 Mar 1966 (ref. 190).
250. Ibid., 4.
251. John C. Gerhart, "How regulative is early amphibian development?," Perspectives on cellular regulation, from bacteria to cancer, essays in honor of Arthur B. Pardee (New York, 1991), 185-200, on 187.
252. Monod wrote of Gerhart in 1965, in response to inquiries about Harvard's appointing him as a protein chemist, "He does not really belong strictly to any single field. I mean that he is not exactly a physico-chemist, but rather an enzymologist and also something of a biochemical geneticist." Letter from Monod to John T. Edsall, 23 Nov 1965, Fonds Monod, Archives de l'Institut Pasteur.
253. Monod's late work on the enzyme phosphofructokinase is an elaboration and demonstration of his mathematical model of 1965 for ligand effects, including only one sentence about the significance of the protein's regulation in the cell's metabolic management. D. Blangy, H. Buc and J. Monod, "Kinetics of the allosteric interactions of phosphofructokinase from Escherichia coli," JMB, 31 (1968), 13-35.
254. To use the language of Monod, the diagram depicts only homotropic, not heterotropic, interactions. In the paper of 1965, Monod, Wyman, and Changeux wrote: "By far the most striking and physically if not physiologically, the most interesting property of allosteric proteins is their capacity to mediate homotropic co-operative interactions between stereospecific ligands," Monod, Wyman, and Changeux (ref. 172), 89. In this vision, heterotropic interactions, which initially defined the second site and allosteric inhibition, are superfluous.
255. Clarke and Fujimura (ref. 6); M. Norton Wise, ed., The values of precision (Princeton, 1995); J.P. Gaudillière and I. Löwy, eds., The invisible industrialist: Manufacturers and the production of scientific knowledge (London, forthcoming).
256. Clarke and Fujimura (ref. 6); M. Norton Wise, ed., The values of precision (Princeton, 1995); J.P. Gaudillière and I. Löwy, eds., The invisible industrialist: Manufacturers and the production of scientific knowledge (London, forthcoming).
257. See Jon Beckwith, "Genetics at the Institut Pasteur, substance and style," ASM news, 53 (1987), 551-55.
258. Monod to Jacob, 29 June 1961, Fonds Monod, Archives de l'Institut Pasteur.