  Given that the development of cancer is an immensely complex causal process that cannot be observed directly, many scientific claims about cancer’s causes are based on indirect inference, using model organisms or cells in culture. For instance, tumors are grown in nude mice using xenotransplantation, or, tumors are observed to grow in mice in which “driver genes” are “knocked out.” Soto and Sonnenschein have argued that the artificial experimental circumstances that have enabled or promoted the study of cancer “genes” render judgments about their causal efficacy suspect; in principle, they claim, it’s consistent with these experiments to suggest that these mutations are mere effects of the true causes of carcinogenesis. Whether or not one agrees with their conclusions about TOFT v. SMT, they do raise methodological questions worth exploring about the scope and limitations of model organism work. Germain (2013) points out that cancer in these xenotransplantation experiments are “highly artificial” contexts, and echoes concerns of researchers that the use of immunodeficient mice to study cancer stem cells, for instance, may or may not warrant the conclusions they claim to establish. Xenotransplantation, for instance, has been used to articulate and test hypotheses about “intrinsic tumorigenicity” of some cells, particularly cells expressing a particular antigen, ABCB5+, which were then designated “cancer stem cells” in light of their capacity to form tumors in nude mice (Germain, 2013, p. 9). The problem with using these tools, however, is that the matter of when and whether a cell is “tumorigenic” varies across different backgrounds—in immune deficient mice, lacking a particular receptor (interleukin-2 gamma receptor, or Il2rg), tumors will grow, but not in mice with such a receptor. Which experimental context is relevant to understanding how and why cancer is caused by “stem cells,” thus depends upon which causes we wish to isolate, and how. As Germain points out,