Version 11 Do reductionist cures select for holistic diseases? Adaptive chronic infection, structured stress, and medical magic bullets Rodrick Wallace The New York State Psychiatric Institute Robert G. Wallace Dept. of Biology City College of New York * December 31, 2003 Abstract With a generalized language-of-thought argument for immune cognition, we model how population-directed structured psy- chosocial stress can impose an image of itself on the coevo- lutionary conflict between a highly adaptive chronic infection and the immune response. We raise the possibility that, for successful ‘evolution ma- chines’ like HIV and malaria, simplistic individual-oriented magic bullet drug treatments, vaccines, behavior modifica- tions, or other interventions that do not address the funda- mental living and working conditions underlying disease ecol- ogy will fail to control current epidemics and may select for holistic pathogenic life histories which increase disease viru- lence. Key words: adaptation, chronic infection, cognition, im- mune, interpenetration, mutator, phase transition, renormal- ization, virulence Introduction The first papers in this series (Wallace and Wallace, 2002; Wallace, 2002a), examined culturally-driven variation in HIV transmission and malaria pathology. HIV responds to im- mune challenge as an evolution machine, generating copious variation and hiding from counterattack in refugia at mul- tiple scales of space, time, and population. P. falciparum engages in analogous rapid clonal antigenic variation, and cyto-adherence and sequestration in the deep vasculature, pri- mary mechanisms for escaping from antibody-mediated mech- anisms of the host’s immune system (e.g. Alred, 1998). Some- thing much like the mutator mechanism, in the sense of Thaler (1999), or ‘second order selection’ in the sense of Tenallion et al. (2001), appears to generate antigenic variation in the face of immune attack for a large class of pathogens. On the other hand, recent work by DiNoia and Neuberger (2002) outlines the mechanisms by which the immune system’s own antibody-producing B-cells engage in a second-order fine tun- ing of antibody production through an exceedingly high rate * Address correspondence to Rodrick Wallace, PISCS Inc., 549 W 123 St., Suite 16F, New York, NY, 10027. Telephone (212) 865-4766, email rdwall@ix.netcom.com. Affiliations are for identification only. of mutation-like transformations, a hypermutation which al- lows us to respond quickly and effectively to pathogens that we have been exposed to previously (Gearhart, 2002). Many chronic infections, particularly those which cloak themselves in antigenic ‘coats of many colors’, are very of- ten marked by distinct ‘stages’ over the course of disease. For HIV this typically involves an initial viremia triggering an immune response that drives the virus into refugia during an extended asymptomatic period which, with the collapse of the immune system, ends in AIDS. Malaria’s most evident ‘stages’ are expressed as explosive outbursts of rapid para- site replication which facilitate insect-mediated transmission between hosts. HIV, malaria, and a third disease, tuberculo- sis, account for over five million deaths a year worldwide and exemplify the evolutionary success of multiple-stage chronic- ity as a life history strategy (Ewald, 2000; Villarreal, et al., 2000). Here we extend the earlier theoretical analysis of Wallace (2002a), which focused on infection as a sudden ‘perturba- tion’. We will analyze how pathogen life history stages repre- sent a kind of evolutionary punctuation (e.g. Eldredge, 1985) for chronic infection in the face of relentless immune and other selection pressure. For HIV that punctuation may arise from the direct interactions between the virus and the immune sys- tem response. In the case of malaria, it may result by means of a ‘second order punctuation’ through the mutator mechanism (Thaler, 1999) associated with rapid antigenic variation. Else- where we study clonal selection in tumorigenesis from such a ‘second order’ perspective (Wallace et al., 2003). It is this interpenetration between antagonistic adaptive processes that so defines disease ecosystems. Adami et al. (2000) applied an information theoretic approach to conclude that genomic complexity resulting from evolutionary adapta- tion can be identified with the amount of information a gene sequence stores about its environment. Lewontin (2000) in essence suggested something of a reverse process, in which en- vironmental complexity represents the amount of information organisms introduce into their environment as a result of their collective actions and interactions. We propose modeling the two ’information sources’ provides a more faithful encapsula- tion of the interactive, multi-scale nature of pathogen-immune 1