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A Knockout Experiment: Disciplinary Divides and Experimental Skill in Animal Behaviour Genetics

  • Nicole C. Nelson

Abstract

In the early 1990s, a set of new techniques for manipulating mouse DNA allowed researchers to ‘knock out’ specific genes and observe the effects of removing them on a live mouse. In animal behaviour genetics, questions about how to deploy these techniques to study the molecular basis of behaviour became quite controversial, with a number of key methodological issues dissecting the interdisciplinary research field along disciplinary lines. This paper examines debates that took place during the 1990s between a predominately North American group of molecular biologists and animal behaviourists around how to design, conduct, and interpret behavioural knockout experiments. Drawing from and extending Harry Collins’s work on how research communities negotiate what counts as a ‘well-done experiment,’ I argue that the positions practitioners took on questions of experimental skill reflected not only the experimental traditions they were trained in but also their differing ontological and epistemological commitments. Different assumptions about the nature of gene action, eg., were tied to different positions in the knockout mouse debates on how to implement experimental controls. I conclude by showing that examining representations of skill in the context of a community’s knowledge commitments sheds light on some of the contradictory ways in which contemporary animal behaviour geneticists talk about their own laboratory work as a highly skilled endeavour that also could be mechanised, as easy to perform and yet difficult to perform well.

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Copyright

Corresponding author

*Email address for correspondence: nicole.nelson@wisc.edu

References

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1. Barinaga, Marcia, ‘Knockouts Shed Light on Learning’, Science, 257, 5067 (1992), 162.

2. Kandel, Eric, Search of Memory (New York: WW Norton, 2006), 291.

3. Tonegawa’s paper was published shortly after the Cold Spring Harbor symposium as Alcino J. Silva, Richard Paylor, Jeanne M. Wehner and Susumu Tonegawa, ‘Impaired Spatial Learning in Alpha-Calcium-Calmodulin Kinase II Mutant Mice’, Science, 257, 5067 (1992), 206–11.

4. Kandel and Soriano’s paper was published several months later as Seth G.N. Grant, Thomas J. O’Dell, Kevin A. Karl, Paul L. Stein, Philippe Soriano and Eric R. Kandel, ‘Impaired Long-Term Potentiation, Spatial Learning, and Hippocampal Development in fyn Mutant Mice’, Science, 258, 5090 (1992), 1903–10.

5. O’Dell, Thomas J., Kandel, Eric R. and Grant, Seth G.N., ‘Long-Term Potentiation in the Hippocampus is Blocked by Tyrosine Kinase Inhibitors’, Nature, 353 (1991), 558560.

6. Grant et al., op. cit. (note 4), 1903.

7. Silva et al., op. cit. (note 3), 210.

8. Ibid.

9. Barinaga, op. cit. (note 1), 162.

10. Asa Abeliovich, Richard Paylor, Chong Chen, Jeansok J. Kim, Jeanne M. Wehner and Susumu Tonegawa, ‘PKC Gamma Mutant Mice Exhibit Mild Deficits in Spatial and Contextual Learning’, Cell, 75, 7 (1993), 1263–71; Asa Abeliovich, Chong Chen, Yukiko Goda, Alcino J. Silva, Charles F. Stevens and Susumu Tonegawa, ‘Modified Hippocampal Long-Term Potentiation in PKC${\it\gamma}$-Mutant Mice’, Cell, 75, 7 (1993), 1253–62; Atsu Aiba, Chong Chen, Karl Herrup, Christian Rosenmund, Charles F. Stevens and Susumu Tonegawa, ‘Reduced Hippocampal Long-Term Potentiation and Context-Specific Deficit in Associative Learning in mGluR1 Mutant Mice’, Cell, 79, 2 (1994), 365–75; Atsu Alba, Masanobu Kano, Chong Chen, Mark E. Stanton, Gregory D. Fox, Karl Herrup, Theresa A. Zwingman and Susumu Tonegawa, ‘Deficient Cerebellar Long-Term Depression and Impaired Motor Learning in mGluR1 Mutant Mice’, Cell, 79, 2 (1994), 377–88.

11. Chong Chen, Donald G. Rainnie, Robert W. Greene and Susumu Tonegawa, ‘Abnormal Fear Response and Aggressive Behavior in Mutant Mice Deficient for Alpha-Calcium-Calmodulin Kinase II’, Science, 266, 5183 (1994), 291–4; Ming Xu, Rosario Moratalla, Lisa H. Gold, Noboru Hiroi, George F. Koob, Ann M. Graybiel and Susumu Tonegawa, ‘Dopamine D1 Receptor Mutant Mice Are Deficient in Striatal Expression of Dynorphin and in Dopamine-Mediated Behavioral Responses’, Cell, 79, 4 (1994), 729–42.

12. Morris, Richard G.M. and Kennedy, Mary B., ‘The Pierian Spring’, Current Biology, 2, 10 (1992), 511514.

13. Anthony Deutsch, J., ‘Spatial Learning in Mice’, Science, 262, 5134 (1993), 760763.

14. Routtenberg, Aryeh, ‘Knockout Mouse Fault Lines’, Nature, 374, 6520 (1995), 314.

15. Harry M. Collins, Changing Order: Replication and Induction in Scientific Practice (London: Sage Publications, 1985); idem, ‘The Seven Sexes: A Study in the Sociology of a Phenomenon, or the Replication of Experiments in Physics’, Sociology, 9, 2 (1975), 205–24; idem, ‘Son of Seven Sexes: The Social Destruction of a Physical Phenomenon’, Social Studies of Science, 11, 1 (1981), 33–62.

16. Interviews were conducted between 2006 and 2010, and the majority of these interviews were conducted under the condition that the material would be used anonymously. This anonymity, while potentially lessening the value of these interviews for historical inquiry, was a necessary precondition for being able to gather this information because of the fears that many practitioners held about the public representation of behaviour genetics and the potential for controversy. All of the excerpts used for this paper come from interviews with researchers in North America who identified as ‘behaviourists’; that is, they had spent the majority of their careers working on questions about behaviour using either genetic or neurobiological approaches.

17. The ethnographic fieldwork that this paper draws on was conducted between 2006 and 2009 in animal behaviour genetics laboratories and scientific meetings, and in particular in laboratories in the department of neuroscience on the west coast of the United States that I refer to here as ‘Western University’. This research was also conducted under the condition that it would be used anonymously, and the name ‘Western University’ is a pseudonym.

18. Rheinberger, Hans-Jörg, ‘What Happened to Molecular Biology?’, BioSocieties, 3 (2008), 303310, here: 304.

19. Abir-Am, Pnina G., ‘The Politics of Macromolecules: Molecular Biologists, Biochemists, and Rhetoric’, Osiris, 7 (1992), 164191.

20. Rassmussen, Nicolas, Gene Jockeys: Life Science and the Rise of Biotech Enterprise (Baltimore: Johns Hopkins University Press, 2014).

21. S. Brenner to M. Perutz, 5 June 1963, cited in Soraya de Chadarevian, ‘Of Worms and Programmes: Caenorhabditis Elegans and the Study of Development’, Studies in History and Philosophy of Biology and Biomedical Sciences, 29, 1 (1998), 81–105.

22. Rachel A. Ankeny, ‘The Natural History of Caenorhabditis elegans Research’, Nature Reviews Genetics, 2 (2001), 474–9; idem, ‘Fashioning Descriptive Models in Biology: Of Worms and Wiring Diagrams’, Philosophy of Science, 67 (Supp., 2000), S260–72. Soraya de Chadarevian has also shown how Brenner’s approach to this new area of study was influenced by his prior work in gene function and protein synthesis, from his choice of a ‘simple’ experimental organism such as C. elegans to his invocation of the notion of a ‘programme’ by which genes controlled development; see de Chadarevian, ibid.

23. John Paul Scott’s experimental work at the Jackson laboratory is a good example of what research in animal behaviour genetics looked like in the post-WWII period. On Scott’s dog breeding experiments, see Diane Paul, ‘The Rockefeller Foundation and the origin of behavior genetics’, in K.R. Benson, J. Maienschein and R. Rainger (eds), The Expansion of American Biology, 231–61. On Scott’s experiments with mice and aggression, see Gregg Mitman, ‘Dominance, Leadership, and Aggression: Animal Behavior Studies During the Second World War’, Journal of the History of the Behavioral Sciences, 26, 1 (1990), 3–16.

24. On the history of twin studies in the United States, see M. Susan Lindee, Moments of Truth in Genetic Medicine (Baltimore: Johns Hopkins University Press, 2008), especially ch. 5. On the different methodological approaches that constitute the heterogeneous field of behaviour genetics, see Aaron Panofsky, Misbehaving Science: Controversy and the Development of Behavior Genetics (Chicago: University of Chicago Press, 2014).

25. Panofksy, ibid., see especially ch. 2.

26. For example, one commonly used test for anxiety, the open field test, was originally developed in the 1930s by psychologist Calvin S. Hall as a test of ‘emotionality’ in rodents. Another common test for anxiety, the light/dark emergence task, was developed in the early 1980s by a behavioural neuroscientist but draws strongly on the social psychologist Kurt Lewin’s theory of approach – avoidance conflicts. For more on how the validity of these tests as models for human anxiety is constructed and maintained, see Nicole C. Nelson, ‘Modeling Mouse, Human, and Discipline: Epistemic Scaffolds in Animal Behavior Genetics’, Social Studies of Science, 43, 1 (2013), 3–29.

27. Fujimura, Joan, ‘Crafting Science: Standardized Packages, Boundary Objects, and “Translation”’, in Pickering, A. (ed.), Science as Culture and Practice (Chicago: University of Chicago Press, 1992), 168211.

28. Panofsky, op. cit. (note 24).

29. The Jackson Laboratory is a non-profit organisation that conducts genetic research using mouse models and provides scientific services to the mouse community (such as providing a centralised repository for mouse strains). For a history of the Jackson Laboratory and its role in the standardisation of the mouse as a model organism, see Karen Rader, Making Mice: Standardizing Animals for American Biomedical Research, 1900–1955 (Princeton: Princeton University Press, 2004).

30. Researcher C, interview, 23 January 2008.

31. Hans-Jörg Rheinberger, ‘Gene concepts: fragments from the perspective of molecular biology’, in P. Buerton et al. (eds), The Concept of the Gene in Development and Evolution (Cambridge: Cambridge University Press, 2000), 219–39.

32. Angela N.H. Creager, The Life of a Virus (Chicago: University of Chicago Press, 2001); Soraya de Chadarevian, Designs for Life: Molecular Biology After World War II (Cambridge: Cambridge University Press, 2002). See also Hans-Jörg Rheinberger, Toward a History of Epistemic Things (Stanford: Stanford University Press, 1997).

33. Paul, op. cit. (note 23). Panofsky, op. cit. (note 24) does take up the question of contacts between behaviour genetics and other fields, but from a sociological perspective.

34. On the prevalence of the ‘neuro’ in contemporary biology, see Nikolas Rose and Joelle M. Abi-Rached, Neuro: The New Brain Sciences and the Management of the Mind (Princeton: Princeton University Press, 2013).

35. Kandel, op. cit. (note 2), see especially chs 20 and 21.

36. Ibid., 289.

37. Two of the four knockout mouse lines used in Kandel’s 1992 paper were developed in Soriano’s laboratory, which Soriano likely provided to Kandel in exchange for co-authorship on the paper. For more on exchange practices within the mouse community, see Fiona Murray, ‘The Oncomouse That Roared: Hybrid Exchange Strategies as a Source of Distinction at the Boundary of Overlapping Institutions’, American Journal of Sociology, 116, 2 (2010), 341–88.

38. Kandel, op. cit. (note 2), 291.

39. See Silva’s autobiographical note on his personal website, http://www.silvalab.org/alcino\_silva.html (accessed 26 January 2015).

40. Peter Mombaerts, Alan R. Clarke, Martin L. Hooper and Susumu Tonegawa, ‘Creation of a Large Genomic Deletion at the T-Cell Antigen Receptor Beta-Subunit Locus in Mouse Embryonic Stem Cells by Gene Targeting,’ PNAS, 88, 8 (1991), 3084–7; Asa Abeliovich, David Gerber, Osamu Tanaka, Motoya Katsuki, Ann M. Graybiel and Susumu Tonegawa, ‘On Somatic Recombination in the Central Nervous System of Transgenic Mice’, Science, 257, 5068 (1992), 404–10.

41. MIT Communications Office (ed.), Reports to the President, 1993 (Cambridge: MIT, 1993), 488; idem, Reports to the President, 1994 (Cambridge: MIT, 1994), 41, 380, 385.

42. This research was conducted in the laboratory of Mario Capecchi, who was one of the recipients of the 2007 Nobel Prize in Physiology or Medicine for this work. See Kirk R. Thomas and Mario R. Capecchi, ‘Targeted Disruption of the Murine Int-1 Proto-Oncogene Resulting in Severe Abnormalities in Midbrain and Cerebellar Development’, Nature, 346, 6287 (1990), 847–50.

43. Pamela L. Schwartzberg, Alan M. Stall, Jeff D. Hardin, Katherine S. Bowdish, Teresa Humaran, Sharon Boast, Margaret L. Harbison, Elizabeth J. Robertson and Stephen P. Goff, ‘Mice Homozygous for the ablm1 Mutation Show Poor Viability and Depletion of Selected B and T Cell Populations’, Cell, 65, 7 (1991), 1165–75; Philippe Soriano, Charles Montgomery, Robert Geske and Allan Bradley, ‘Targeted Disruption of the C-Src Proto-Oncogene Leads to Osteopetrosis in Mice’, Cell, 64, 4 (1991), 693–702.

44. Crawley, Jacqueline N. and Paylor, Richard, ‘A Proposed Test Battery and Constellations of Specific Behavioral Paradigms to Investigate the Behavioral Phenotypes of Transgenic and Knockout Mice’, Hormones and Behavior, 31 (1997), 197211.

45. Jacqueline N. Crawley, interview, 21 November 2007.

46. Abir-Am, op. cit. (note 19).

47. Panofsky, op. cit. (note 24) describes the late 1980s and early 1990s as a time of both excitement and anxiety in behaviour genetics because of the rapid advances in the molecular techniques. He argues that techniques brought new money into the field at a time when NIH grants for behaviour genetics were in decline but also generated tensions between veteran behaviour geneticists and the new entrants to the field.

48. Dorothy Nelkin and M. Susan Lindee, The DNA Mystique: The Gene as a Cultural Icon (New York: Freeman, 1995); Lindee, op. cit. (note 24).

49. Steven Hyman, ‘Using genetics to understand human behavior: promises and risks’, in Erik Parens, Audrey R. Chapman and Nancy Press (eds), Wrestling with Behavioral Genetics: Science, Ethics and Public Conversation (Baltimore: Johns Hopkins University Press, 2006), 109–30, here: 109–10.

50. Cohen, Jon, ‘Share and Share Alike Isn’t Always the Rule in Science’, Science, 268, 5218 (1995), 17151718.

51. Crawley and Paylor, op. cit. (note 44), 205.

52. Ibid., 206, 197.

53. The textbook contains an introductory note welcoming molecular geneticists to the world of behavioural neuroscience while at the same time warning them that behavioural testing is too complex to be undertaken without an experienced collaborator. See Jacqueline N. Crawley, What’s Wrong with My Mouse? Behavioral Phenotyping of Transgenic and Knockout Mice (New York: Wiley-Liss, 2000), 3.

54. Collins, Changing Order, op. cit. (note 15).

55. Collins, ‘Son of Seven Sexes’, op. cit. (note 15), 34.

56. Gerlai, Robert, ‘Gene-targeting Studies of Mammalian Behavior: Is It the Mutation or the Background Genotype?’, Trends in Neurosciences, 19, 5 (1996), 177181, here: 181.

57. Ibid., 179. On the confounds complicating the assessment of learning and memory performance in knockout mice see also Hans-Peter Lipp and David P. Wolfer, ‘Genetically Modified Mice and Cognition’, Current Opinion in Neurobiology, 8, 2 (1998), 272–80.

58. Cold Spring Harbor Laboratory Annual Report 1996 (Cold Spring Harbor: CSHL Archives, 1996), 304–5.

59. Silva, Alcino J., Simpson, Elizabeth M., Takahashi, Joseph S., Lipp, Hans-Peter, Nakanishi, Shigetada, Wehner, Jeanne M., Giese, Karl P., Tully, Tim, Abel, Ted, Chapman, Paul F., Fox, Kevin, Grant, Seth, Itohara, Shigeyoshi, Lathe, Richard, Mayford, Mark, McNamara, James O., Morris, Roger J., Picciotto, Marina, Roder, John, Shin, Hee-Sup, Slesinger, Paul A., Storm, Daniel R., Stryker, Michael P., Tonegawa, Susumu, Wang, Yanyan and Wolfer, David P., ‘Mutant Mice and Neuroscience: Recommendations Concerning Genetic Background’, Neuron, 19, 4 (1997), 755759.

60. Ibid.

61. Crawley, Jacqueline N., Belknap, John K., Collins, Allan, Crabbe, John C., Frankel, Wayne, Henderson, Norman, Hitzemann, Robert J., Maxson, Stephen C., Miner, Lucinda L., Silva, Alcino J., Wehner, Jeanne M., Wynshaw-Boris, Anthony and Paylor, Richard, ‘Behavioral Phenotypes of Inbred Mouse Strains: Implications and Recommendations for Molecular Studies’, Psychopharmacology, 132 (1997), 107124.

62. Ibid., 120.

63. Wim E. Crusio, ‘Gene Targeting Studies: New Methods, Old Problems’, Trends in the Neurosciences, 19, 5 (1996), 186–7, quote: 187. The original EGF study is Maria Sibilia and Erwin F. Wagner, ‘Strain-Dependent Epithelial Defects in Mice Lacking the EGF Receptor’, Science, 269, 5221 (1995), 234–8.

64. Gerlai, op. cit. (note 56), 180.

65. Ankeny, ‘Fashioning Descriptive Models’, op. cit. (note 22).

66. Crusio, op. cit. (note 63), 187.

67. Ibid.

68. Xu et al., op. cit. (note 11); John Drago, Charles R. Gerfen, Jean E. Lachowicz, Heinz Steiner, Tom R. Hollon, Paul E. Love, Guck T. Ooi, Alexander Grinberg, Eric J. Lee, Sing Ping Huang, Perry F. Bartlett, Pedro A. Jose, David R. Sibley and Heiner Westphal, ‘Altered Striatal Function in a Mutant Mouse Lacking D1A Dopamine Receptors’, PNAS, 91, 26 (1994), 12564–8.

69. Sylvie Ramboz, Frédéric Saudou, Djamel Aït Amara, Catherine Belzung, Louis Segu, René Misslin, Marie-Christine Buhot and René Hen, ‘5-HT$_{1\text{B}}$ Receptor Knock Out – Behavioral Consequences’, Behavioural Brain Research 73, 1–2 (1995), 305–12; Xiaoxi Zhuang, Cornelius Gross, Luca Santarelli, Valerie Compan, Anne-Cécile Trillat and René Hen, ‘Altered Emotional States in Knockout Mice Lacking 5-HT1A or 5-HT1B Receptors’, Neuropsychopharmacology, 21 (1999), 52S–60S. The conflict between these two results is noted in Deborah A. Finn, Mark T. Rutledge-Gorman and John C. Crabbe, ‘Genetic Animal Models of Anxiety’, Neurogenetics, 4, 3 (2003), 109–35.

70. Finn et al., ibid.

71. Crabbe, John C., Wahlsten, Douglas and Dudek, Bruce C., ‘Genetics of Mouse Behavior: Interactions with Laboratory Environment’, Science, 284, 5420 (1999), 1672.

72. Ibid.

73. Wahlsten, Douglas, Metten, Pamela, Phillips, Tamara J., Boehm II, Stephen L., Burkhart-Kasch, Sue, Dorow, Janet, Doerksen, Sharon, Downing, Chris, Fogarty, Jennifer, Rodd-Henricks, Kristina, Hen, René, McKinnon, Carrie S., Merrill, Catherine M., Nolte, Cedar, Schalomon, Melike, Schlumbohm, Jason P., Sibert, Jason R., Wenger, Charlotte D., Dudek, Bruce C. and Crabbe, John C., ‘Different Data from Different Labs: Lessons from Studies of Gene–Environment Interaction’, Journal of Neurobiology, 54, 1 (2003), 283311, here: 305.

74. Ibid., 306.

75. Gerlai, Robert, ‘Gene Targeting: Technical Confounds and Potential Solutions in Behavioral Brain Research’, Behavioural Brain Research, 125, 1–2 (2001), 1321.

76. Ibid., 15.

77. Greenspan, Ralph J., ‘A Kinder, Gentler Genetic Analysis of Behavior: Dissection Gives Way to Modulation’, Current Opinion in Neurobiology, 7 (1995), 805811.

78. Ibid., 811.

79. Nelson, Nicole C., ‘Shooting Genes, Distributing Credit: Narrating the Development of the Biolistic Gene Gun’, Science as Culture, 21, 2 (2012), 205232.

80. Collins, ‘Son of Seven Sexes’, op. cit. (note 15); Collins, Changing Order, op. cit. (note 15).

81. Collins, Changing Order, op. cit. (note 15), 84.

82. For a definition of the ‘core set’, see ibid., 142–5.

83. Researcher A, interview, 25 August 2006.

84. Researcher D, interview, 6 January 2009.

85. Graduate Student A, interview, 8 April 2008.

86. Researcher A, op. cit. (note 83).

87. Researcher E, interview, 14 August 2006.

88. Rheinberger, op. cit. (note 32).

89. See for example Collins, Harry M., de Vries, G. H. and Bijker, Wiebe E., ‘Ways of Going On: An Analysis of Skill Applied to Medical Practice’, Science, Technology & Human Values, 22, 3 (1997), 267285.

90. Graduate Student A, op. cit. (note 85).

91. For an excellent description of how mechanisation has been employed in genomics, see Hallam Stevens, ‘On the Means of Bio-Production: Bioinformatics and How to Make Knowledge in a High-Throughput Genomics Laboratory’, BioSocieties, 6 (2011), 217–42.

92. Researcher F, interview, 19 July 2006.

93. Rheinberger, Toward a History of Epistemic Things, op. cit. (note 32).

Thanks to Harald Kliems for his research assistance and to Thomas Schlich and Nicholas Whitfield for creating a welcoming space for cross-disciplinary discussions on skill and for providing helpful comments throughout the revision process. I would also especially like to thank Thomas Broman for reading multiple versions of this paper and offering thoughtful suggestions on how best to frame it. This project was funded by a Doctoral Dissertation Improvement Grant from the National Science Foundation (Award No. SES 0749635) and a Doctoral Fellowship by the Social Sciences and Humanities Research Council of Canada.

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A Knockout Experiment: Disciplinary Divides and Experimental Skill in Animal Behaviour Genetics

  • Nicole C. Nelson

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