Property:Pre-meeting notes
From Complex Time
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Dynamic Multi-System Resilience in Human Aging/Emergence of Aging in Natural and Synthetic Multicellular Structures +
# Evolution of interdependence. Neutral constructive evolution ties genes/cells/tissues/organisms together. A random walk in the space of networks leads to the most likely arrangement: random networks.
# Statistics of catastrophes in interdependent systems: Gompertz law, dynamics that are qualitatively independent of network structure and model details.
#Aging in synthetic tissues. Cells die at a slower rate when allowed to exchange goodies. Intercellular interactions are more important than chronological age or damage agents. Failures propagates from outwards in. Edges and boundaries are more susceptible to failure.
#Failure as a microscope: Failure times can be used to infer the structure of interdependence networks.
Many simple organisms such as ferns, hydra or jellyfish do not age. Their mortality rates remain approximately constant at all ages. In contrast, complex organisms typically have a probability of death m(t) that increases with age, t. Furthermore, the functional form of m(t) for many different organisms show a remarkable degree of similarity. The difference between simple and complex organisms, and the universality of aging patterns among complex organisms strongly suggest that aging is an emergent phenomenon that depends not on the individual properties of biological building blocks,but rather, on the interactions between them. Indeed, we die not because we slowly run out of live cells, but because of systemic failures that manifest in complex organs. In this talk I will present a quantitative theory of aging based on evolutionary and mechanical arguments, and show how aging appears as an emergent phenomenon as one moves across the scale of complexity, from large molecules and cells, to tissues and organs. I will particularly focus on aging in synthetic tissues, since this is the simplest structure that admits controlled experimental observation of emergent systemic damage. I will end my talk by showing how failure can be used as a "microscope". Specifically, how failure times can inform us about the structure of the interdependence network.
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''Elizabeth Klerman – Review of mathematical models of circadian rhythms''
I will review current mathematical models of circadian rhythms, their inputs, outputs, and structure and then areas in which new work is needed – especially adjustment of models to predict inter-individual differences rather than describe group averages.
''Cecilia Diniz Behn - Modeling interactions between circadian rhythms and sleep''
In mathematical models of sleep, representations of circadian rhythmicity determine sleep timing under both entrained and perturbed conditions. I will review the role of circadian rhythms in sleep/wake models and the ways in which the complexity of these representations crucially affects sleep/wake dynamics. +
''Gina Poe – Sleep is for forgetting''
It is possible that one of the essential functions of sleep is to take out the garbage, as it were, erasing and “forgetting” information built up throughout the day that would clutter the synaptic network that defines us. It may also be that this cleanup function of sleep is a general principle of neuroscience, applicable to every creature with a nervous system. I will discuss the importance of forgetting for development, memory integration and updating, and for resetting sensory-motor synapses after intense use. Sleep states and traits that could serve this unique forgetting function may be different for memory circuits within reach of the locus coeruleus (LC) vs. those formed and governed outside its noradrenergic net. Specifically, I will talk about the role of rapid eye movement (REM) and transition-to-REM (TR) sleep for hippocampal and somatosensory memories and the role of non-REM sleep for memories guided by the dorsal striatum (e.g., motor and procedural learning).
''Susan Sara - Locus coeruelus in time with the making of memories during sleep''
Experience -related reactivation of neuronal ensembles during sleep is a well-established phenomenon. It occurs mainly during high frequency sharp wave ripples in the hippocampus, but has been shown to occur in neocortical regions as well. The current belief is that newly formed synapses in replay ensembles are reinforced through a potentiation process. We have revealed an increase in firing rate of noradrenergic neurons of the locus coeruleus (LC) during nonREM sleep after learning and a temporal relationship between LC spiking and cortical slow waves and spindles. Release of Norepinephrine by LC neurons in time with these oscillations could promote synaptic plasticity and facilitate sleep-dependent memory consolidation. +
What is Sleep?/How does zooming out to look across species help us to then zoom in on sleep function? +
''Jerry Siegel –'' A popular approach to investigating sleep function is to deprive people, or animals, of sleep and note the changes that emerge. However, sleep deprivation is necessarily stressful, no matter how gentle the stimuli applied, making it unclear if the observed effects are due to cortisol release or other aspects of the procedure. Sleep duration in animals varies from 2 to 20 hours, with a proportionate range in REM sleep amounts. This variation can be correlated with other aspects of physiology to gain an insight into the evolutionary determinants of sleep without the confounds resulting from deprivation. I will briefly review the animal sleep literature.
''Alex Herman, Van Savage -'' Sleep is a nearly ubiquitous and evolutionarily ancient process experienced by multicellular animals. Despite the enormous diversity of animals that sleep and the huge range in time scale for different aspects of sleep--total time, REM, circadian--systematic patterns emerge that suggest unifying underlying principles when viewed in the correct mathematical and conceptual spaces. Linking these large-scale patterns to theories about their biological and biophysical origins allows us to derive equations that shed insight into how sleep varies across species. Thus, finding the right lens with which to “zoom in” requires first “zooming out”. To that effect we show that the total time spent sleeping and the length of sleep cycles vary as power-laws with body size across about 6 orders of magnitude. Building on prior allometric scaling theory, we are able to predict these power-laws based on a theory for the central role of repair in sleep. Scaling according to these patterns reveals, for instance, that herbivores display significantly less variability in sleep times than carnivores or omnivores, potentially yielding insight into differential evolutionary pressures on sleep function. Moreover, we have recently examined how sleep time and cycle length vary as humans grow in body and brain size, as opposed to the commonly used chronological age. We find two distinct scaling regimes that emerge from the data and are separated by a distinct transition. We are able to predict these scaling regimes and the transition with reasonable accuracy by using a theory--supported by experimental data--that in early life sleep serves primarily to facilitate changes in synaptic density and white matter connectivity, while in later life the process of sleep is dominated by maintenance and repair. Our theory helps lay the groundwork for understanding both individual ontogenetic-growth and across-species variation in brain development and sleep dynamics, yielding a powerful new lens with which to zoom in on the functions of sleep.
''Sara Aton – ''The essential role of network oscillations for sleep-dependent memory consolidation
Our laboratory is addressing how sleep contributes to memory consolidation and associated synaptic plasticity in the mouse brain. We hypothesize that some forms of brain plasticity occur preferentially during sleep due to its unique patterns of network activity. Here, I'll discuss our use of optogenetic tools to silence or rhythmically activate subsets of neurons involved in generating sleep-associated thalamocortical network oscillations. We are studying how these manipulations affect both neural and behavioral plasticity. In thalamocortical circuits following novel sensory experiences, we find increases in the coherence of network oscillations during sleep that predict subsequent plasticity. Disruption of these oscillations leads to a loss of plasticity and a failure in long-term memory formation. We have also found that selective reactivation of sensory neurons engaged during prior learning is essential for sleep-dependent consolidation of sensory-cued memories. We hypothesize that sleep-associated network oscillations promote stable reactivation of neuronal ensembles, which in turn drives synaptic plasticity and long-term memory storage across brain circuits.
''Kimberley Whitehead - Why are brain oscillations important to the function of sleep in early life?''
Sleep dominates early life, during which rapid eye movement (REM) sleep occupies a far greater proportion of sleep time than later in development. Thalamo-cortical oscillations are spatially and temporally organised by sleep-wake state in neonatal mammals, including humans. For example, somatosensory cortical oscillations occur preferentially following REM sleep-associated twitches, and subserve the refinement of neural body maps. Therefore sleep-related brain oscillations in early life may index sensorimotor functional development.
In adults, the intensity of slow wave oscillations during non-REM sleep has been used to model the pressure to sleep, and its restorative functions, but in neonates slow wave oscillations are prevalent during each sleep state, and even wakefulness. I will discuss the challenges of modelling sleep-wake organisation in pre-term human infants, in whom classical brain oscillations such as the alpha rhythm of wakefulness and the slow waves and sleep spindles of non-REM sleep are absent.
What is Sleep?/What’s the best level or timescale for modeling sleep or do we need to integrate them all? +
''Victoria Booth - A case for ntegrating all time scales: sleep-wake temporal architecture across development and aging''
It is well documented that duration, timing and the level of fragmentation of sleep change across development and aging. Some studies have looked more closely at sleep-wake temporal architecture and identified finer timescale changes that occur over development. Statistical analyses of the distributions of sleep and wake bout durations in rodents show that both sleep and wake bouts display exponential distributions in infancy but the wake bout distribution shifts to a power-law or multiexponential distribution with development. This qualitative difference in sleep and wake bout distributions has likewise been observed in adult humans and other mammals. In adult sleep, wake, NREM and REM sleep bout distributions have distinct properties which are additionally modulated across the 24h day due to the circadian rhythm. With further aging, NREM bout distributions change due to increased fragmentation of that state. The different bout length distribution profiles for wake, NREM and REM sleep suggest that these states are regulated by different physiological mechanisms, and the changes in distribution profiles across development and aging presumably reflect changes in those regulatory mechanisms. This begs the question: can tracking bout duration distributions across development and aging provide insight into the structure of the underlying physiological mechanisms governing sleep regulation? +
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Cognitive Regime Shift I - When the Brain Breaks/Large-scale Brain Network Changes Across the Healthy Adult Human Lifespan: Relations to Cognition and First Steps toward Identifying Potential Risk Factors of Brain Decline +
-Human brain areas are organized into a large-scale functional network, which can be measured at rest using non-invasive brain imaging (functional MRI)
-The brain network contains segregated sub-networks that correspond to functionally specialized brain systems
-The segregation of brain systems declines with increasing age, across the healthy adult lifespan
-System segregation relates to cognitive function in individuals (greater system segregation is associated with better long--term memory ability)
-Certain health risk factors (e.g., lower socioeconomic status) are related to lower system segregation
-My working hypothesis is that gradual and sudden cognitive decline is related to changes in system segregation as an individual ages, and that individual differences in rate and risk of decline are a consequence of the capacity of the functional brain network to tolerate and adapt to damage (neurodegeneration) +
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Dynamic Multi-System Resilience in Human Aging/Multiscale modeling to help making sense of dynamical multiscale resilience +
A generic approach towards multiscale modelling will be introduced, together with examples from modelling complex multiscale physiological processes. Next, based on an admittedly shallow literature review, a possible extension of this methodology towards modelling dynamical multiscale resilience will be proposed. Finally, challenges in mapping these concepts to Dynamic Multi-System Resilience in Human Aging will be discussed. +
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Aging and Adaptation in Infectious Diseases II/Session I: Immune System: Architecture and Dynamics#Allometric Scalings and Immune Dynamics +
A key lesson from allometric scaling perspectives has been that a variety of physiological processes and timescales systematically change with body size. These have important implications for interpreting a variety of ecological processes and for normalizing physiology across diverse organisms. Applying these concepts to infectious disease may, on the practical side, make it possible to scale interventions between organisms of very different size, and on scientific side, help us to systematize the ecology and evolution of hosts and parasites. In this talk we will discuss: 1) how various immune dynamics can be systematically scaled with body size and what implications this may have for organism physiology, 2) the time-scales of infection across diverse organisms, 3) the consequences of infection on lifetime reproduction across organisms of different size and across different broad taxonomic groups, and 4) the efficacy of vaccines and the timescales of immunity. +
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A large number of neurodegenerative diseases feature the accumulation of mis-folded proteins. These include prion diseases, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. In all of these cases several different scales of organization are associated with disease progression or onset to include genetic, epigenetic, neural circuits, brain modules, and behavior. How should we best integrate data from each of these levels and what models and theories allow us to span levels? I shall discuss a few dynamical models of polymerization, protein accumulation, and protein diffusion through neural connections, that provide insights into disease progression at a number of different time and space scales. An ongoing challenge is a criterion for fixing thresholds that define an observable cognitive regime shift. +
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African killifishes independently evolved annual life cycles at least three times, offering a unique natural experiment of diversification of life history strategies. Using a comprehensive whole-genome sampling of 46 species of African killifishes, we found that genome size correlates with annual life style and climate. Annual species had genome-wide expansion of transposable elements, higher gene family turn-over rates and relaxed selection in genes in known aging pathways, such as mitochondrial replication and translation, mTOR pathway and DNA repair. Whole-genome resequencing in wild ''Nothobranchius'' populations showed bottle-necks and a genome-wide signature of relaxation of selection in populations evolved in dryer climates. In conclusion, evolution in ephemeral environments in African killifishes caused an extensive relaxation of selective constraints at genome-wide level. We discovered that, in African killifishes, ecology drove the evolution of short life span and rapid aging, associated to tens of thousands of slightly deleterious mutations driven to high frequencies. +
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Dynamic Multi-System Resilience in Human Aging/Studies of Resiliencies to Physiologic Stressors: Need for Multilevel and Life Course Approaches +
Age-related declines in resiliencies can contribute to a variety of adverse health and functional outcomes in later life. Consequently, it can be more difficult for an older person to recover from acute illnesses or injuries which are otherwise efficiently resolved or overcome by younger individuals. For the purposes of this discussion, resilience is defined as a dynamic property which enables cells, organs, organisms or individuals to resist or recover from the effects of a physiologic/physical stressor. To gain meaningful insight into the various aspects of aging changes in resiliencies to physical stressors, such as the diversity of resilient phenotypes, the underlying protective factors which preserve resilience with aging (or conversely risk factors that contribute to vulnerabilities) and the trajectories of change in these factors with age, it will be important for studies to incorporate multilevel and life course approaches.
Regarding multilevel examinations, examples of clinical assessments which can be leveraged as dynamic measures of resiliencies spanning the whole-body to physiological systems include perturbation tests of balance, assessments of cognitive processing speed following chemotherapy, methacholine tests and tilt-table testing. Yet, the current lack of standardized research tools to probe resiliencies at the cellular level is a major methodological hurdle to research on resiliencies and aging. A crucial feature of such assays will be the ability to quantitatively assess cellular resilience in a person-specific manner. To this end, the literature contains examples of in vitro tests which may be adapted and validated for cellular resiliencies, such as assays of DNA repair capacity to predict sensitivity to chemotherapeutic agents, immune profiling methods to predict recovery post hip replacement, and scratch wound migration assays to predict recovery from surgical procedures. Commonly used in vitro tests of cellular stress responses in biology of aging research (e.g., resistance to oxidative stress, inflammatory cytokine production, activation of anti-apoptotic pathways) may also serve as a basis for the development of standardized assays. Once available, these standardized tests of cellular resilience could be further translated into a novel class of personalized in vitro clinical diagnostics.
Moreover, insight into changes in resiliencies across the human lifespan (a gerontological perspective) could reveal aging mechanisms underlying decrements, as well as factors contributing to the maintenance of resilient phenotypes as we age. Data from the field of regenerative medicine suggest that there may be intrinsic factors present during postnatal growth and development which confer greater resiliency in juveniles compared to adults. Specifically, data generated in various animal models indicate that juvenile organisms possess more robust defense mechanisms and more efficient repair mechanisms (though it is acknowledged that immaturity can also be associated with increased vulnerability). In summary, the characterization of different resilient phenotypes and elucidation of age-related changes in resiliencies to specific stressors and the underlying mechanisms (cellular resiliencies) at different stages of the life span could create new translational research opportunities for the development of novel, targeted interventions to preserve and/or enhance resiliency and for promoting healthy aging in humans.
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Hallmarks of Biological Failure/Systems-Level Modeling of Aging across Biological Levels of Organization +
Aging is associated with numerous changes at all levels of biological organization. Harnessing this information to develop measures that accurately and reliably quantify the biological aging process will require incorporation of functioning/failure at various levels that can be integrated using systems level approaches. This talk will provide illustrations on how DNA methylation data (DNAm) can be integrated with cellular, physiological, proteomic, and clinical data to model age-related changes that propagate up the levels—finally manifesting as age-related disease or death. We will also show how network modeling can be used to generate a ‘diseasome’ model in order to identify hub methylation signatures with implication for multiple pathways and outcomes. Given the complexity of the biological aging process, modeling of systems dynamics over time will both lead to the development of better biomarkers of aging, and also inform our conceptualization of how alterations at the molecular level propagate up levels of organization to eventually influence morbidity and mortality risk. +
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Irreversible Processes in Ecological Evolution/Are changes in species interactions and their ecosystem consequences irreversible? +
All interactions between individuals of the same or different species (populations) are metabolically-constrained. That is, the rate of an individual's energy use (metabolic rate) sets the rate of interactions with other individuals. In this talk, I will first describe the relationship between metabolic and species interaction rates as a function of the physical environment as well as the organism's mass, using ecological metabolic theory. I will then describe the effects of (metabolically-constrained) species interactions on the dynamics of ecosystems. Finally, I will consider whether changes in metabolically-constrained species interactions are irreversible. +
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All life requires the capacity to recover from challenges that are as inevitable as they are unpredictable. Understanding this resilience is essential for managing the health of humans and their livestock. It has long been difficult to quantify resilience directly, forcing practitioners to rely on indirect static indicators of health. However, measurements from wearable electronics and other sources now allow us to analyze the dynamics of physiology and behavior with unsurpassed resolution. The resulting flood of data coincides with the emergence of novel analytical tools for estimating resilience from the pattern of micro-recoveries observed in natural time series. Such dynamic indicators of resilience (DIORs) may be used to monitor the risk of systemic failure across systems ranging from organs to entire organisms. These tools invite a fundamental rethink of our approach to the adaptive management of health and resilience. +
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Population and the Environment: Analytical Demography and Applied Population Ethics/Co-evolution of population and environment - perceiving climate change and its impacts on reproduction and migration +
Among the biggest puzzles in studies of climate change is why so many people support policies and politicians that appear to undermine their own best interests. These have been identified across the world, including in the US, where advocates for science in climate studies and action find themselves locked in battle with climate-change deniers. While these things can be addressed under classic rubrics of rationality, questions of meaning, nature, and what we tend to take for granted are equally important. Through what cultural frames – whether expressed through local, international, legal or scientific idioms – can we best grasp how people are responding to what we might see as dangerous climate change and the best solutions to it? While easy answers to these questions are illusive, findings from analogous studies – child fosterage, Western contraceptive use, and migration from West Africa to Europe and the US – may be brought to bear to address some of the principles on which they seem to rest. +
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Aging and Adaptation in Infectious Diseases II/Session II: Immune System: Aging and Heterogeneity#Original antigenic sin and antigenic maps +
Antigenic mapping is an important technique used measure and visualize differences between viruses, but understanding how these maps change given immune system variation between individuals remains challenging. Do the immune systems of different individuals see the same virus differently? How does this perspective change as individuals age and experience different sets of viruses in different orders? We briefly touch on some approaches we've taken to answer these questions and suggest how exposure history might affect both individual immune responses and epidemiological patterns. +
Aging and Adaptation in Infectious Diseases/Session IV: Complex Rhythms, environment, and aging in epidemiology#Insights into aging and pathogens from allometrically scaled models for host-parasite systems +
Assemble a talk that describes non-human examples of how host exposure and response to pathogens and disease changes with age.
Describe ways of quantifying age-dependent changes in exposure.
Discuss possible dynamic consequences in variation in duration of incubation and infectivity with age.
Describe models for parasitic nematodes of different sizes living as a community of worms in hosts of different sizes.
Illustrate recent work with Ian Hatton on body size scaling of vital rates from Algae to Elephants - use this to suggest we could use this scaling for models of immune system in mammals (from bats and mice to elephants and whales). +
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Irreversible Processes in Ecological Evolution/Cooperative growth and cell-cell aggregation in marine bacteria +
Bacterial cooperation, whereby cells secrete compounds that can facilitate the growth of neighboring cells, has been extensively studied through the lens of evolutionary biology. However, the environmental implications of cooperation and the ecological scenarios under which it takes place remain much less understood. In this talk I will discuss the conditions under which cooperative growth emerges in microbial populations that degrade complex organic materials in the ocean. I will show that organisms that are poor secretors of hydrolytic enzymes use chemotactic behavior to form cell-cell aggregates that enable individuals to increase local concentrations and efficiently uptake the solubilized organic matter. By contrast, when organisms secrete highly active enzymes dynamics turn competitive, cells avoid aggregation and the efficiency of carbon uptake drops. I will also discuss the theoretical limits of aggregation and how bacterial isolates from the ocean overcome these limits in the laboratory by developing multicellular behaviors. I will back up these results with theory, data from individual based models and experiments with natural isolates. Finally, I will discuss the potential role of social cheaters in the natural environment, based on a study with hundreds of micro-scale particle colonization experiments in natural seawater. +
