Notes: Interlude: Calling Them Home

Chapter notes for “Interlude: Calling Them Home”

Notes

¹⁵ Bianconi, E. et al., “An estimation of the number of cells in the human body,” Annals of Human Biology 40:6 (2013): 463–471. The 37 trillion estimate; refined by Sender, R. and Milo, R., “The distribution of cellular turnover in the human body,” Nature Medicine 27 (2021): 45–48, to ~30–37 trillion depending on sex and body size. The classical histological count of ~200 cell types is being expanded by the Human Cell Atlas project, which identifies subtypes at finer molecular resolution.

¹⁶ Driesch, H., “Entwicklungsmechanische Studien: I. Der Werth der beiden ersten Furchungszellen in der Echinodermenentwicklung,” Zeitschrift für wissenschaftliche Zoologie 53 (1891): 160–184. The foundational experiment in regulative embryology: separated blastomeres at the two-cell stage each developed into complete, smaller pluteus larvae. Replicated across multiple sea urchin species including Paracentrotus lividus and Hemicentrotus pulcherrimus.

¹ Chernet, B.T. and Levin, M., “Transmembrane voltage potential is an essential cellular parameter for the detection and control of tumor development in a Xenopus model,” Disease Models & Mechanisms 6 (2013): 595–607. Forced hyperpolarisation via misexpression of specific ion channels suppressed oncogene-induced tumor formation. The mechanism: hyperpolarisation drives SLC5A8-mediated butyrate influx, inhibiting histone deacetylase (HDAC), causing cell cycle arrest. See also Levin, M., “Bioelectric signaling: Reprogrammable circuits underlying embryogenesis, regeneration, and cancer,” Cell 184 (2021): 1971–1989.

² Loewenstein, W.R. and Kanno, Y., “Intercellular communication and the control of tissue growth: Lack of communication between cancer cells,” Nature 209 (1966): 1248–1249. The first demonstration that tumor cells lack the electrical coupling that characterizes normal tissue — a finding whose implications for cancer-as-coordination-failure took decades to develop.

³ Davies, P.C.W. and Lineweaver, C.H., “Cancer tumors as Metazoa 1.0: tapping genes of ancient ancestors,” Physical Biology 8 (2011): 015001; updated in Lineweaver, C.H., Bussey, K.J., Blackburn, A.C., and Davies, P.C.W., “Cancer progression as a sequence of atavistic reversions,” BioEssays 43 (2021): e2000305. Phylostratigraphic analysis confirms that cancer cells overexpress evolutionarily ancient genes while suppressing genes associated with multicellular coordination.

⁴ Strassmann, J.E., Zhu, Y., and Queller, D.C., “Altruism and social cheating in the social amoeba Dictyostelium discoideum,” Nature 408 (2000): 965–967. See also Aktipis, C.A. et al., “Cancer across the tree of life: cooperation and cheating in multicellularity,” Philosophical Transactions of the Royal Society B 370 (2015): 20140219. Aktipis frames cancer explicitly as cheating against the multicellular cooperative contract.

⁵ Aasen, T. et al., “Connexins in cancer: bridging the gap to the clinic,” Oncogene 38 (2019): 4429–4451. Connexin downregulation is a hallmark of primary tumors; paradoxical re-expression in metastasis facilitates endothelial adhesion and intravasation. See also Sinyuk, M. et al., “Cancer Connectors: Connexins, Gap Junctions, and Communication,” Frontiers in Oncology 8 (2018): 646.

⁶ Davidenko, J.M. et al., “Stationary and drifting spiral waves of excitation in isolated cardiac muscle,” Nature 355 (1992): 349–351. Re-entrant spiral autowaves in cardiac tissue underlie ventricular tachycardia and fibrillation — pathologies of rhythm, not of energy supply.

⁷ Fajgenbaum, D.C. and June, C.H., “Cytokine storm,” New England Journal of Medicine 383 (2020): 2255–2273. Cytokine storms represent loss of immune refractory control — positive feedback without negative regulation, producing systemic hyperactivation that damages host tissue.

⁸ Dustin, M.L., “The immunological synapse,” Cancer Immunology Research 2 (2014): 1023–1033. The immunological synapse is a structured signaling interface where TCR microclusters form centripetal actin-driven waves.

⁹ Sharpe, A.H. and Pauken, K.E., “The diverse functions of the PD1 inhibitory pathway,” Nature Reviews Immunology 18 (2018): 153–167. PD-1/PD-L1 interaction recruits SHP-2 phosphatase, dephosphorylating ZAP70 and CD3ζ, directly quenching TCR signaling.

¹⁰ Joyce, J.A. and Fearon, D.T., “T cell exclusion, immune privilege, and the tumor microenvironment,” Science 348 (2015): 74–80. The tumor microenvironment as immunosuppressive field: TGF-β, adenosine (CD73/CD39 axis), regulatory T-cells, and myeloid-derived suppressor cells each raising the local excitation threshold for immune activation.

¹¹ Ngwa, W. et al., “Using immunotherapy to boost the abscopal effect,” Nature Reviews Cancer 18 (2018): 313–322. The abscopal effect (regression of distant, untreated tumors following local therapy) is consistent with systemic re-excitation of the immune surveillance autowave.

¹² Wallace, R., Cognitive Dynamics on Clausewitz Landscapes: The Control and Directed Evolution of Organized Conflict (Springer, 2020). The critical stability criterion ατ < e⁻¹ ≈ 0.368 derives from the Data Rate Theorem (Nair et al. 2007) applied to cognition/regulation dyads under conditions of friction and delay. See also the annex on collective intelligence experiments in this volume for the full treatment of Wallace’s framework.

¹³ Lo-Coco, F. et al., “Retinoic acid and arsenic trioxide for acute promyelocytic leukemia,” New England Journal of Medicine 369 (2013): 111–121. Differentiation therapy (coaxing cancer cells to mature rather than destroying them) achieves cure rates exceeding 90% in APL, the clearest clinical example of re-coordination outperforming elimination.

¹⁴ Ribas, A. and Wolchok, J.D., “Cancer immunotherapy using checkpoint blockade,” Science 359 (2018): 1350–1355. Checkpoint immunotherapy produces durable remissions in melanoma, non-small-cell lung cancer, and other tumors, with some patients maintaining complete responses for over a decade — a durability profile that chemotherapy rarely achieves.

¹⁷ Kirson, E.D. et al., “Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors,” Proceedings of the National Academy of Sciences 104 (2007): 10152–10157. The foundational demonstration that low-intensity, intermediate-frequency (200 kHz) alternating electric fields disrupt cell division through dielectrophoretic forces on polar molecules, particularly tubulin dimers and septin complexes. For a comprehensive mechanism review, see Rominiyi, O. et al., “The Mechanisms of Action of Tumor Treating Fields,” Cancer Research 82 (2022): 3650–3658. FDA approval of the Optune device for newly diagnosed glioblastoma followed in 2015.

¹⁸ Stupp, R. et al., “Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial,” JAMA 318 (2017): 2306–2316. The EF-14 phase III trial: median overall survival 20.9 months with tumor treating fields plus temozolomide versus 16.0 months with temozolomide alone (HR 0.63, p = 0.004). Five-year survival rate 13% with TTFields versus 5% without. Compliance above 90% usage time raised median survival to 24.9 months, underscoring the dose-response relationship central to the chapter’s argument: the longer the coordination signal is maintained, the more durable the outcome.

¹⁹ Jobson, S., Montgomery, E.M., Hamel, J.-F., Sipler, R.E., and Mercier, A., “Natural tissue immortality: Indefinite survival of sea cucumber explants,” Science Advances 12:22 (2026): eaeb1394. DOI: 10.1126/sciadv.aeb1394. The species itself has been known since the nineteenth century; what was described in 2026 is the survival of its discarded tissue. Explanted epidermal, connective, neural, and muscle tissue from Psolus fabricii healed and continued to grow in natural, non-sterile seawater, without supplementation, for more than three years, showing immune activity, cell cycling, tissue reorganization, and absorption of dissolved amino acids in place of feeding. Muscle cells were broken down from within by coelomocytes while connective tissue and collagen expanded to fill the space, which is what gives the explants their near-spherical form. Equivalent explants from related echinoderms did not survive, the paper reporting no comparable tissue survival in them. Press coverage of the study puts the longest at about 104 days, a figure the abstract itself does not carry.