The search for the hematopoietic stem cell: immunology and epistemic success

1. The search for the hematopoietic stem cell: immunology and epistemic success Melinda B. Fagan January 30, 2007 Presented to: Program in Science and Technology Studies University of California, Davis

2. Outline: I. Framework: science as social action II. Empirical case study: the search for HSC a. selection of case b. methods c. results III. Significance: epistemic success

3. Framework: starting point Empirical studies show that our scientific practices are suffused with social interactions and sociological influences. Scientific knowledge results from these pervasively social practices. Scientific knowledge is intentionally produced by our practices - not an automatic or accidental byproduct. Therefore, scientific practices are social actions, with scientific knowledge as their goal.

4. Minimal consensus: • difference concerns practical reasoning • shared goals and participant means • instrumentally rational social action requires: - achievable shared goal - coordinated participant means Theories of social action: Aim: explanatory account of the difference between individual and social action Theories of social action: • individually inadequate; complementary • multilevel explanatory framework for social action • empirical study of particular cases required for explanation

5. Empirical study of social action: Empirical studies of particular cases of social action describe: (1) levels of participation involved (‘groups within groups’) (2)shared goals (3) interactions among individuals and groups that coordinate means to shared goals (4) standards for successful achievement of shared goals

6. Immunology: study of structure and function of the immune system

7. Science as social action: immunology (1)levels of participation (2)shared goal (3)interactions among individuals and groups working to achieve shared goals (4)successful achievement of shared goals • individuals, within-lab groups, between-lab groups, labs, sub-fields, fields, disciplines From: Lucille Packard Children’s Hospital, Stanford Dept. of Oncology •understanding the immune system & treatment of infectious diseases, autoimmune disorders, cancers • Fleck (1935), Moulin (1989), Löwy (1992), Keating & Cambrosio (2003) • clonal selection theory, immunoglobulin genes, B &T lymphocytes, complement, histocompatibility, antigen processing and presentation, cytokine signaling

8. Science as social action: the search for HSC (1)levels of participation (2)shared goal (3)interactions among individuals and groups (4)successful achievement of shared goals • individuals, within-lab groups, between-lab groups, labs, sub-fields, fields, sub-disciplines “The isolation of a pure population of self-renewing pluripotent hematopoietic stem cells is a requirement for understanding the developmental biology of the hematolymphoid system, and also would be instrumental for a number of gene, cell, and organ replacement clinical therapies dependent on bone marrow transplantation.” • within and among lab groups; within and across sub-disciplinary boundaries • focus on: 1981-1988 • a “turning point in modern immunology” (Immunological Reviews 2002, no. 185)

9. Interviews and laboratory visits: (1) details concerning social interactions (2) participants’ attitudes toward shared goals, means, success (3) multiple perspectives on the episode: involvement, role, subsequent career path Empirical study: the search for the HSC Methods: examination of published literature (2) interviews with participating researchers (3) first-hand experience in the Weissman lab

10. Empirical study: outline (1) search for HSC - ‘pre-Weissman phase’ (2) crucial interactions in Weissman group’s search (3) 1988 result and reception (4) epistemic success in the search for HSC

11. Empirical study: the search for the HSC (early 1960s) HSC capacities: (1) immune reconstitution (2)multi-potency (3) self-renewal Spleen colonies: T cells B cells M-E cells

12. spleen colonies (quantitative assay) cell size/density anti-mitotic drugs HSC research community (ca. 1968):

13. ‘environment’ immunomagnet Lin- FACS mAb Sca-1 B T M-E B T M-E negative selection strategy lineage progenitor assays 1988 result Spangrude Klein Aihara Heimfeld Coffman Whitlock Ezine … Whitlock Müller-Sieburg HSC: the Weissman group’s search (1980s) From: University of Birmingham, MRC Centre for Immune Regulation T cell development Weissman Gutman

14. The search for the HSC: 1988 result “the degree of enrichment of activities is consistent with the hypothesis that all Thy-1loLin-Sca-1+ cells are HSC” (Spangrude et. al., 1988, 58-59) “the only true pluripotent stem cells in the bone marrow” (Spangrude et. al., 1988, 61) “isolation of a pure population of self-renewing pluripotent hematopoietic stem cells” (Spangrude et. al. 1988, 58)

15. Reception of the 1988 result: 1988 (Science) “Did the Weissman group make a real contribution in the mouse? No, not at all. All of the work had already been done elsewhere.” Malcolm Moore (quoted in Radetsky 1995, 91) 1984 (Journal of Experimental Medicine)

16. Examination of the 1988 success X (1) 10-fold greater enrichment of HSC from mouse bone marrow (2) new model of blood cell development, coordinating HSC capacities with cell phenotype (3) new direction and impetus for the search for HSC (with therapeutic emphasis)

17. 1968 - spleen colonies 1989 - the turning point 2000 - finer distinctions Search for the HSC: models of hematopoiesis From: Weissman 2000 From: Spangrude 1989

18. The search for HSC: epistemic success by coordinated means Coordination: • collaborative interactions within and among lab groups (coordination of practices) • critical interactions at new interfaces between groups (coordination of standards) Result: • increasingly detailed model of hematopoeisis, coordinating cell phenotype, molecular and genetic mechanisms, cell development, immune reconstitution

19. The above are taken as participant means to the shared epistemic goal of scientific inquiry. Empirical studies of science: general result Two kinds of success: (1) construction of improved models of subject matter of inquiry (2) formation of new interfaces with other lines of inquiry Requirements for instrumentally rational social action: coordinated participant means achievable shared goal √

20. Social action: minimal requirements Coordinated participant means: If scientific success proceeds by the coordinated means of model-construction and interface-formation, then the diverse groups to which a successful model will be accountable cannot be specified in advance. Achievable shared goal: If scientific practices are minimally instrumentally rational, then they have a shared goal that is achievable by these coordinated means.

21. Therefore, the shared goal of scientific practices is knowledge independent of epistemic criteria specific to particular groups. Scientific objectivity: The shared goal of scientific practices is knowledge such as to possibly result from coordinated model-construction and interface-formation. If these means are coordinated, then the epistemic standards successful models must satisfy cannot be specified in advance. Therefore, the shared goal of scientific practices is knowledge such as to possibly satisfy epistemic standards not specifiable in advance. Scientific objectivity: science aims at knowledge independent of the opinions of any single individual or group of individuals.

22. Summary and conclusion: • two mutually exclusive projects: - scientific practices or detached epistemic ideals • empirical case study of science as social action - minimal framework of shared goals, participant means - social interactions and scientific success • integrative result: an account of scientific objectivity grounded (implicit) in our scientific practices

23. Colin Allen Michael Bratman Jordi Cat Steve Crowley Tom Gieryn Elihu Gerson Mark Kaplan Acknowledgements: The National Science Foundation Louise McNutt Dissertation Year Fellowship (IUB) Robert Coffman George Gutman Motonari Kondo Libuse Jerabek Sean Morrison Jerry Spangrude Irv Weissman Adam Leite Elisabeth Lloyd Helen Longino Jutta Schickore Fred Schmitt Rob Skipper