To the editor—In his commentary on self organization, complexity and chaos in biological systems1, Coffey states that tumors are models of chaos, whereas normal tissues are characterized by order. Although this is probably true of epithelial tumors, in mesenchyme-derived cancers, such as acute leukemias and lymphomas, quite the opposite may be found. Normal hematopoiesis and immunity are best described by chaos, with myriad clones evolving and differentiating according to a stochastic model, a characteristic that endows this system with its incredible versatility in coping with the constant variability of the antigenic spectrum. For example, the genetic instability of the variable regions of the immunoglobulin and T-cell receptor genes is the premise on which specific antibody and cell mediated immune responses are based.

In contrast, leukemia, lymphoma and myeloma cells are monoclonal, with a relative morphologic, immunophenotypic and genetic uniformity. Of course, if this homogeneity were absolute, chemotherapy results would be better that they are. However, the leukemic clone retains a certain degree of chaos, and can therefore eventually adapt to new conditions, ultimately resulting in emerging resistance. It is, however, notable that normal hematopoiesis exposed during chemotherapy to cytotoxic damage will recover in a matter of weeks (because of its versatility resulting from increased chaos), whereas the resistance of a neoplastic clone will appear in months or years. Indeed, in a small but significant percentage of patients that can actually be cured by chemotherapy, resistance may never appear.

This pattern is even more evident for malignant lymphoma; many of these patients are actually cured by cytotoxic drugs. In fact, it is a mystery why an orderly system like a hematopoietic tumor gains any growth advantage in the fist place over such a versatile, chaotic system as normal hematopoiesis. One possible explanation is an incapacity of the normal clones to deal with a certain damaging condition, resulting in a Darwinian natural selection of 'defective' clones that may eventually become malignant. For example, paroxysmal nocturnal hemoglobinuria (PNH), a clonal hematologic disease associated with increased leukemia risk, can be explained by such processes: the PNH clone has been shown to lack a set of receptors through which a subset of abnormal autoimmune cytotoxic T lymphocytes destroys the normal hematopoietic stem cells, thus offering a relative growth advantage for the PNH 'defective' cells2. Further clonal selection in this more orderly system (more order means less competition, therefore a better chance for a given clone to gain advantage), may lead to a premalignant myelodysplastic syndrome or to overt leukemia. As in social and political systems, controlled chaos is less likely than totalitarian order to produce the over-focused ideologies and trends that can give rise to cataclysmic events.

See “In reply to 'Chaos in cancer?' “ by Donald S. Coffey