https://orcid.org/0000-0001-5504-608X
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ABSTRACT
Genetically modified or ‘transgenic’ mice are a routine experimental tool in biomedical research, commonly produced by injecting DNA into one-cell embryos. These animals were independently invented in 1980 by multiple university groups in the United States and Europe that combined expertise in mouse developmental biology and recombinant DNA techniques, or ‘genetic engineering’. In this article, I examine this multiple invention and argue that research strategies, experimental practices, and funding arrangements that led to transgenic mice are best described as tinkering. These creative and speculative endeavors, combined with partial knowledge of what was happening in competing laboratories, created a fruitful atmosphere for research which led to the multiple invention. The tinkering was, however, underpinned by infrastructures that were crucial to success, some long established, such as mouse supply or embryological tools, and some emerging, such as the informal exchange of isolated genes.
Acknowledgements
I wish to thank Nick Hopwood, Dominic Berry, Sarah Franklin, Jean-Paul Gaudillière, Martin Johnson, Jesse Olszynko-Gryn, Harriet Palfreyman, Karen Rader, Tiago Saraiva, Jim Secord, Kathryn Schoefert, and the anonymous referee for their advice and insightful comments on the manuscript in its various stages. I also with to thank Karen Rader for her kind perseverance in putting together this special issue.
Disclosure statement
No potential conflict of interest was reported by the author.
Notes
1. For trends in the UK, largely representatives of countries with significant biomedical research, see http://www.understandinganimalresearch.org.uk/animals/numbers-animals/.
2. Rader, Making Mice.
3. “Products of the Year,” Fortune, 5 December 1988.
4. Merton, Sociology of Science; and Murray, “Oncomouse That Roared.”
5. Brannigan, Social Basis of Scientific Discoveries.
6. Bud, Uses of Life.
7. de Chadarevian, “Of Worms and Programmes”; Morange, “Transformation of Molecular Biology”; on developmental biology as a superdiscipline, see Hopwood, “Inclusion and Exclusion.”
8. Lévi-Strauss, Savage Mind, 16–17.
9. Knorr, “Tinkering toward success.”
10. Curry, Evolution Made to Order, 78–129. See also Lavine, “Something about X-rays.”
11. Harper, Working Knowledge, 74.
12. Creager and Landecker, “Technical Matters.”
13. Jacob, “Evolution and Tinkering.”
14. Ibid., 1163.
15. Morange, “French Tradition.”
16. Brenner, “Introduction,” 2. The symposium was dedicated to the retirement of Sir Gordon Wolstenholme, the Ciba Foundation’s director and chairman of the UK Genetic Manipulation Advisory Group, which explains its comparatively ambitious topic.
17. Kevles, “Renato Dulbecco”; and Scheffler, “Managing the Future.”
18. Krimsky, Genetic Alchemy; and Wright, Molecular Politics.
19. Gurdon et al., “Sexually Mature Individuals.” For Gurdon’s microinjection work, see e. g. Lane et al., “Rabbit Haemoglobin Synthesis”; and Mertz and Gurdon, “Purified DNAs.”
20. De Robertis et al., “Injected Living Cells.” See also Gurdon, “Molecular Biology in a Living Cell.” With the spread of DNA cloning, Xenopus oocytes were also envisioned as a promising system to track the elusive promoters, DNA sequences upstream of a gene that control its expression.
21. Porter and O’Connor, Human Genetics, 60.
22. Developments in Cell Biology, 6.
23. Examining the link between development and cancer was an important tradition at the Fox Chase Institute for Cancer Research; see Crowe, “Cancer, Conflict.”
24. Mintz, “Gene Expression.”
25. Mintz, “Teratocarcinoma Cells.”
26. See Kolata, Clone, 103–133.
27. Illmensee, “Genetic Manipulation.”
28. Dawid and Wahli, “Application of Recombinant DNA.”
29. Tim Stewart, interviewed by the author on 31 May 2012.
30. Morange, “Transformation of Molecular biology;” de Chadarevian, “Mapping Development”; and Yi, “Cancer, Viruses, and Mass Migration.”
31. Greenberg, “Bootlegging.”
32. Brinster and Arechaga, “Embryo Culture.”
33. Frank Ruddle, interviewed by the author on 8 December 2011.
34. Brinster and Arechaga, “Embryo Culture.”
35. The rabbit beta globin RNA came from Jerry Lingrel, a molecular biologist at the University of Cincinnati. Gurdon and Lingrel had published work on injecting the mouse and rabbit beta globin RNA into oocytes, that relied on the latter scientist’s novel method for purifying these molecules: Gurdon et al., “Message Stability.” The second RNA Brinster used was for a Xenopus 5S ribosomal component, which came from another Gurdon collaborator, Donald Brown. The HSV-tk gene was a gift from Carlo Croce of the Wistar Institute down the road.
36. Brinster and Arechaga, “Embryo Culture,” 868. Palmiter, interviewed by the author on 8 June 2012.
37. Brinster et al., “Translation of Globin Messenger RNA.”
38. Pellicer et al., “Introduction of a Viral Thymidine Kinase Gene.”
39. Stewart interview; Erwin Wagner, interviewed by the author on 22 February 2013.
40. Paul Berg to William Gartland, 5 February 1979, Paul Berg Papers. Available online though the National Library of Medicine Profiles in Science: http://profiles.nlm.nih.gov/ps/access/CDBBGT.pdf. Accessed on 9 August 2013.
41. Rudolf Jaenisch, interviewed by the author on 29 January 2013.
42. In his recollections, Mario Capecchi implied that he pointed Ruddle towards microinjection at a 1978 meeting in Portugal (Capecchi, “Gene Targeting”). While Capecchi’s suggestion and early results in cell culture may have been influential, Ruddle did not recall it in the interview, and as evidenced by Diacumakos’ daily planner, he may have been aware of her work as early as 1974. Elaine Diacumakos papers, RU450, Rockefeller Archives, Terrytown, NY.
43. Corvini, “Restrictions Governing DNA Research Eased.”
44. Ruddle interview.
45. Not to be confused with John Gurdon.
46. Wagner and Yun, “Fine structure.” The DNA break hypothesis has not been accepted, with current consensus stating that the super-tight packaging is achieved by replacing histones – normal chromosomal proteins that neutralise the nucleic acid negative charge and coiled DNA – with smaller protamines.
47. Thomas Wagner, interviewed by the author on 25 January 2013.
48. Keith Willison, interviewed by the author on 12 September 2013.
49. Harbers et al., “Microinjection of Cloned Retroviral Genomes,” 542.
50. Not all groups contributed to GEIS – for instance, Brinster did not – but the publication was then in terminal decline, with the final issue published in 1981. Crowe, “General Embryological Information Service.”
51. Brinster et al., “Mouse Oocytes,” 398.
52. U. S. Department of Health and Human Services, Recombinant DNA Research, 59. On the Goodman-Genentect conflict, see Kevles, “Patents, Protections, and Privileges,” 77–94.
53. Willison, “Microinjection of Mammalian Eggs,” 160.
54. Stewart interview.
55. Hopwood, “Inclusion and Exclusion.”
56. de Chadarevian, “Of Worms and Programmes,” “Mapping Development”; and Morange, “François Jacob’s Lab.”
57. Landecker, Culturing Life. See also Wilson, Tissue Culture.
58. Korzh and Strähle, “Marshall Barber.”
59. El-Badry, Micromanipulators and Micromanipulation, 22–72.
60. Hamburger, Heritage of Experimental Embryology;and Gardner, “Mouse Chimaeras.”
61. In 1979, the eminent geneticist James Crow said ‘Karl Illmensee has the embryological equivalent of a green thumb. He actually does the experiments everyone else talks about’ – cited in ‘On the Way to a Clone.’ On the other hand, Mintz was reportedly rather critical of Illmensee in private conversations once he had left Fox Chase. The golden hands argument later was pivotal to Illmensee’s defense in the face of fraud allegations about his nuclear transfer work. On micromanipulation and mammalian embryology, see also Franklin, “’Crook’ pipettes”; and Biological Relatives, ch. 3.
62. See note 45 above.
63. De Robertis et al., “Injected Living Cells”; andMueller et al., “Microinjection.”
64. Landecker, Culturing Life, 212–18.
65. See e.g. McKinnel, Cloning, 118: ‘Certainly, one of the virtues of the [Xenopus oocyte] test system is that it is natural. A nucleus is asked how it will perform in a milieu of normal and unmutilated cytoplasm.’
66. Diacumakos, “Introduction of Macromolecules,” 97–98.
67. John Gordon, interviewed by the author on 10 December 2011.
68. See note 55 above.
69. ‘In general, oocytes are very much more tolerant to injection than fertilized eggs, which are best injected at the 2-cell stage’; Willison, Microinjection of Mammalian Eggs.
70. Diacumakos et al., “Microsurgical Methoidology”; also emphasised in Diacumakos, “Introduction of Macromolecules.”
71. Whittingham and Biggers, “Fallopian Tube”; Whitten and Biggers, “Complete Development in Vitro”; and Biggers, “Reflections.”
72. On the origins of the recombinant DNA exchange and its crucial role in the invention of these tools, see Yi, Recombinant University, 83–112.
73. Pellicer et al., “Introduction of a Viral Thymidine Kinase Gene”; and Scangos et al., “Molecular Analysis.”
74. E. Wagner interview.
75. Brinster and Arechaga, “Embryo Culture”; Palmiter interview.
76. Tofano et al., “Edwin Southern.”
77. Lynch and Jordan, “Sociology of a Genetic Engineering Technique.”
78. ‘I do not look at how a knowledge claim travels from A to B, but at how the transactions made possible by the fact that A and B are distant from each other allow for the production at such a knowledge claim.’ Biagioli, Galileo’s Instruments of Credit, 26. I thank Robin Scheffler for pointing me in this direction.
79. Gordon and Ruddle, “Integration and Stable Germ Line Transmission.”