What complex systems offers to evolutionary medicine
A symposium at the Conference on Complex Systems 2015
8:30-5:00 Wednesday, September 30, 2015
Redrock Room Doubletree Conference Center Tempe, Arizona

Organizers
Randolph Nesse, Arizona State University
Ken Buetow, Arizona State University
Manfred Laubichler, Arizona State University and The Santa Fe Institute
Sander Van Der Leeuw, Arizona State University and The Santa Fe Institute

Abstract
This symposium will explore the synergies possible at the intersections of evolutionary biology and complex systems theory. Applications of evolutionary biology in medicine are growing fast but are only now incorporating advances in the analysis of complex systems. The range of applications is wide. Gene networks are characterized by complexity vastly different from that of designed systems, resulting in both robustness and special vulnerability. Complex networks of positive and negative feedback loops regulate genomic, cellular and physiological systems whose disruption results in disease that can manifest at all these levels. Therapeutic interventions can disrupt these networks in ways that can be useful, but that can also result in additional risks that require understanding in complex systems terms. Cancer is increasingly recognized as an evolutionary process with profound stochasticity. Network analysis offers new insights into the relationships among symptoms of mental disorders. Within the broader context of medicine, systems of medical care organization evolve and grow as well, creating sudden transitions that can undermine the quality of patient care.  We anticipate this symposium will create new connections and projects at the evmed CAS interface.
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Schedule
8:30

Carl Bergstrom*, Erick Chastain, Rustom Antia *University of Washington Defensive complexity and the evolution of vertebrate adaptive immunity

Ken Buetow, Arizona State University
Emergence observed through gene networks: a critical driver of complex disease phenotypes
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9:30
Panel Discussion/Audience engagement on the topic, How many different kinds of opportunities are there at the EvMed CAS interface? Each contributor to the Workshop will offer a 1 minute summary of envisioned opportunities, then the audience will divide into small groups, each led by a speaker for a 20 minute discussion. At 10:00 speakers will come back to the stage to summarize and organize the landscape of ideas and opportunities available at the intersection of evolutionary biology, medicine, and complex systems.

10:30 Break

11:00
Jay Schulkin, Georgetown University Department of Neuroscience, Georgetown University, School of Medicine, Washington DC 20016, USA
Evolutionary conservation of glucocorticoids and corticotropin releasing hormone: Behavioral and physiological adaptations

Randolph Nesse, Center for Evolution & Medicine, School of Life Sciences, Arizona State University
Intrinsically vulnerable facultative adaptations: Implications for medicine
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12:00  LUNCH

1:00
Athena Aktipis, Arizona State University
Cooperation and cheating in complex multicellularity

Carlo Maley, Arizona State University
Surprises from complex systems modeling of the somatic evolution of cancers

2:00
Eiko Fried, University of Lueven, Belgium
A complex dynamic systems perspective on Major Depression

Panel Discussion

3:00 Break

3:30
Sander Van Der Leeuw, Arizona State University and The Santa Fe Institute
Complex Systems Theory and Evolutionary Medicine: the societal dimension

Manfred Laubichler, Arizona State University and The Santa Fe Institute
Disease as an evolving complex system

 

 

 

 

Presentations

 

Athena Aktipis, Arizona State University

Cooperation and cheating in complex multicellularity

 

Multicellularity is the ultimate complex system.  It is characterized by extraordinarily high levels of cooperation and coordination among cells for the development, maintenance and reproduction of the multicellular organism. Cancer can be viewed as cheating within this cooperative multicellular system. Complex multicellularity, and the cooperation underlying it, has evolved independently multiple times. We reviewed cancer-like phenomena across the tree of life and found that cancer is characterized by a breakdown of the central features of cooperation that characterize multicellularity, including cheating in proliferation inhibition, cell death, division of labour, resource allocation and extracellular environment maintenance (which we term the five foundations of multicellularity). Understanding cancer as a breakdown of multicellular cooperation provides novel insights into cancer hallmarks and suggests a set of assays and biomarkers that can be applied across species and characterize the fundamental requirements for generating a cancer.

 

Carl Bergstrom*, Erick Chastain, Rustom Antia *University of Washington

Defensive complexity and the evolution of vertebrate adaptive immunity

One strategy for winning a coevolutionary struggle is to evolve rapidly. Most of the literature on host-pathogen coevolution focuses on this phenomenon, and looks for consequent evidence of coevolutionary arms races. An alternative strategy, less often considered in the literature, is to deter rapid evolutionary change by the opponent. To study how this can be done, we construct an evolutionary game between a controller that must process information, and an adversary that can tamper with this information processing. In this game, a species can foil its antagonist by processing information in a way that is hard for the antagonist to manipulate. We show that the structure of the information processing system induces a fitness landscape on which the adversary population evolves. Complex processing logic can carve long, deep fitness valleys that slow adaptive evolution in the adversary population. We suggest that this type of defensive complexity on the part of the vertebrate adaptive immune system may be an important element of coevolutionary dynamics between pathogens and their vertebrate hosts.

 

 

Ken Buetow, Arizona State University

Emergence observed through gene networks: a critical driver of complex disease phenotypes.

Evolutionary concepts and their related modeling promise to provide critical insight into biologic systems and disease.  Complex disease phenotypes – obesity, type II diabetes, cancer, and complex processes – development, multicellularity, eusociality challenge simple models in both evolution and biology.   Examination of molecular networks and their dynamic behavior offers a means to capture gene-centric concepts and complex, emergent behavior.    Examination of patterns of gene variation which appear chaotic and noisy when examined at the individual gene level show coherence when examined in biological network context.  More specifically, in breast cancer and liver cancer, networks provide much stronger signals of disease susceptibility than individual variants. These analyses show emergent, higher-level association of non-syntenic gene variation. When examining multiple type II diabetes data sets, consistent, recurrent collections of networks predict susceptibility where previous single gene analysis found no overlap.  These interactions demonstrate the emergence of the underlying complex processes important in determining phenotype.

 

Eiko Fried, University of Lueven, Belgium

A complex dynamic systems perspective on Major Depression

 

The standard interpretation of the relationship between a disorder and its symptoms is that the former causes the latter; this routine assumption also applies to mental disorders such as Major Depression (MD). From this perspective, depression symptoms function as passive and somewhat equivalent indicators of their shared latent origin, and are used to assess depression. A different approach is to consider MD as a complex dynamic system in which symptoms interact with each other. This network framework challenges the role of symptoms as passive indicators, and instead conceptualizes them as active agents that have important causal influence. Here we use the network approach to tackle two important and unresolved questions. First, are specific depression symptoms more central in driving depressive processes? Second, are MD symptoms as defined in the DSM-5 more central than non-DSM symptoms common among depressed patients such as anxiety and irritability? To answer these questions, we estimated a network structure of 28 depression symptoms (15 DSM, 13 non-DSM) in a sample of 3,463 depressed patients, and computed the node strength centrality for each symptom (the connectedness with all other symptoms). Symptoms differed considerably in their centrality values, and DSM symptoms were not substantially more central than non-DSM symptoms. The findings suggest the value of research focusing on especially central symptoms to increase the accuracy of predicting outcomes such as the course of illness, probability of relapse, and treatment response.

 

Stephanie Forrest, SFI and University of New Mexico (tentative)

 

Manfred Laubichler, Arizona State University and The Santa Fe Institute

Disease as an evolving complex system

 

Traditional conceptions of disease focus on malfunctioning of otherwise adapted systems and, in the case of infectious diseases, also on the dynamics of populations. In all cases, disease is seen as a departure from an equilibrium state, either of an individual or of a population.

In this talk I will approach disease from an evolving complex systems perspective and develop a conceptual and theoretical framework to look at disease states as evolutionary stages of complex systems.

Such a perspective has implication for how one approaches diseases. Some of those will be sketched as well

 

 

Carlo Maley, Arizona State University

Surprises from complex systems modeling of the somatic evolution of cancers

 

Abstract: Cancers develop through a process of somatic evolution among cells, embedded in a complex ecology of cell types and tissues in an organ. We have used computational, agent-based models of this process to explore current theories of cancer. These models have led to a number of surprises: (1) current methods for inferring the order of events in carcinogenesis are almost always misleading, (2) loss of differentiation is probably the first event in the evolution of most tumors and is a missing hallmark of cancer, (3) the mystery behind the stem cell hypothesis of cancer is the persistence of non-stem cells, though this may be explained by the evolution of proto-multicellularity within neoplasms, (4) the rate of evolution likely speeds up during progression, (5) selective interference is likely much more common than selective sweeps in neoplasms.

 

Randolph Nesse, Center for Evolution & Medicine, School of Life Sciences, Arizona State University

Intrinsically vulnerable facultative adaptations: Implications for medicine

 

A major focus for evolutionary medicine has been how natural selection shapes mechanisms that regulate facultative responses, especially defensive responses such as vomiting or the fight-flight response. A signal detection analysis reveals that optimal systems give rise to many false alarms, a phenomenon described as the Smoke Detector Principle. However, some systems enter runaway positive feedback loops, such as in panic disorder or cytokine storm. This presentation offers mathematical models describing the characteristics of systems that are intrinsically vulnerable because their thresholds adjust adaptively to increased sensitivity on repeated arousal. This phenomenon is likely to provide explanations for vulnerability to anxiety disorders and chronic pain. The tradeoffs involved are likely to constrain selection for mechanisms that adjust thresholds or response intensity as a function of experience in a particular environment.

 

 

Sander Van Der Leeuw, Arizona State University and The Santa Fe Institute

Complex Systems Theory and Evolutionary Medicine: the societal dimension

 

Other papers in this session focus on the biological dimensions of evolutionary medicine, and the impact thereon of complex systems theory. This paper will widen the system under consideration to the socio-environmental context of evolving medical disorders. The classic case in point is that of obesity and the set of disorders that are associated with it (Brewis-Slade 2010), but it is argued here that we must systematically take the societal context into account when studying disorders from an evolutionary perspective. The upsurge in malaria in PNG is directly related to deforestation as a result of western colonisation. Charles Mann argues brilliantly in his two books ‘1491’ and ‘1493’ how European impact in the Americas has decimated the original population and fundamentally transformed the ecosystem. Examples such as these are of particular relevance to Evolutionary Medicine, particularly at an age where technological intervention in the traditional relationship between people and their environment through the consumption of food is under pressure from the political necessity to ensure food security.

 

Jay Schulkin, Georgetown University Department of Neuroscience, Georgetown University, School of Medicine, Washington DC 20016, USA

Evolutionary conservation of glucocorticoids and corticotropin releasing hormone: Behavioral and physiological adaptations

Glucocorticoids and corticotropin releasing hormone (CRH) underlie the physiology of change and adaptation. Both the steroid and peptide are quite ancient. The genes that underlie the production of these information molecules stretch back millions of years. The regulatory mechanisms of glucocorticoids have both restraining and enhancing capabilities on CRH gene expression. While restraint of CRH by glucocorticoids is a fundamental physiological feature of limiting CRH expression from over-use and exhaustion, CRH is also enhanced by glucocorticoids at both the level of extra-hypothalamic CRH sites and at the level of the placenta and fetal programming in the brain. This latter function of glucocorticoids increasing CRH gene expression underlies the physiology of change that underlies diverse adaptive functions.

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