Compulsive over-consumption of rewards characterizes disorders ranging from binge eating to drug addiction. Here, we provide evidence that enkephalin surges in an anteromedial quadrant of dorsal neostriatum contribute to generating intense consumption of palatable food. In ventral striatum, mu opioid circuitry contributes an important component of motivation to consume rewards [1–4]. In dorsal neostriatum, mu opioid receptors are concentrated within striosomes that receive inputs from limbic regions of prefrontal cortex [5–13]. We employed advanced opioid microdialysis techniques that allow detection of extracellular enkephalin levels. Endogenous >150% enkephalin surges in anterior dorsomedial neostriatum were triggered as rats began to consume palatable chocolates. By contrast, dynorphin levels remained unchanged. Further, a causal role for mu opioid stimulation in over-consumption was demonstrated by observations that microinjection in the same anterior dorsomedial quadrant of a mu receptor agonist (DAMGO) generated intense >250% increases in intake of palatable sweet food (without altering hedonic impact of sweet tastes). Mapping by “Fos plume” methods confirmed the hyperphagic effect to be anatomically localized to the anterior medial quadrant of the dorsal neostriatum, whereas other quadrants were relatively ineffective. These findings reveal that opioid signals in anteromedial dorsal neostriatum are able to code and cause motivation to consume sensory rewards.
In multicellular organisms, cell-cell junctions are involved in many aspects of tissue morphogenesis. α-catenin links the cadherin-catenin complex (CCC) to the actin cytoskeleton, stabilizing cadherin-dependent adhesions.
To identify modulators of cadherin-based cell adhesion, we conducted a genome-wide RNAi screen in C. elegans and uncovered MAGI-1, a highly conserved protein scaffold. Loss of magi-1 function in wild-type embryos results in disorganized epithelial migration and occasional morphogenetic failure. MAGI-1 physically interacts with the putative actin regulator AFD-1/afadin; knocking down magi-1 or afd-1 function in a hypomorphic α-catenin background leads to complete morphogenetic failure and actin disorganization in the embryonic epidermis. MAGI-1 and AFD-1 localize to a unique domain in the apical junction and normal accumulation of MAGI-1 at junctions requires SAX-7/L1CAM, which can bind MAGI-1 via its C-terminus. Depletion of MAGI-1 leads to loss of spatial segregation and expansion of apical junctional domains and greater mobility of junctional proteins.
Our screen is the first genome-wide approach to identify proteins that function synergistically with the CCC during epidermal morphogenesis in a living embryo. We demonstrate novel physical interactions between MAGI-1, AFD-1/afadin and SAX-7/L1CAM, which are part of a functional interactome that includes components of the core CCC. Our results further suggest MAGI-1 helps to partition and maintain a stable, spatially ordered apical junction during morphogenesis.
Circadian (~24hr) rhythms offer one of the best examples of how gene expression is tied to behavior. Circadian pacemaker neurons contain molecular clocks that control ~24hr rhythms in gene expression that in turn regulate electrical activity rhythms to control behavior.
Here we demonstrate the inverse relationship: there are broad transcriptional changes in Drosophila clock neurons (LNvs) in response to altered electrical activity, including a large set of circadian genes. Hyperexciting LNvs creates a morning-like expression profile for many circadian genes while hyperpolarization leads to an evening-like transcriptional state. The electrical effects robustly persist in per0 mutant LNvs but not in cyc0 mutant LNvs suggesting that neuronal activity interacts with the transcriptional activators of the core circadian clock. Bioinformatic and immunocytochemical analyses suggest that CREB family transcription factors link LNv electrical state to circadian gene expression.
The electrical state of a clock neuron can impose time-of-day to its transcriptional program. We propose that this acts as an internal zeitgeber to add robustness and precision to circadian behavioral rhythms.
Early Drosophila embryogenesis is characterized by shifting from astral microtubule-based to central spindle-based positioning of cleavage furrows. Before cellularization, astral microtubules determine metaphase furrow position by producing Rappaport-like furrows, which encompass rather than bisect the spindle. Their positioning is explained by our finding that the conserved central spindle components centralspindlin (mKLP1 and RacGAP50C), Polo, and Fascetto (Prc1) localize to the astral microtubule overlap region. These components and the chromosomal passenger complex localize to the central spindle, though no furrow forms there. We identify the maternally supplied RhoGEF2 as a key factor in metaphase furrow positioning. Unlike the zygotic, central spindle-localized RhoGEF (Pebble), RhoGEF2 localizes to metaphase furrows, a function distinct from RhoGEF/Pebble and likely due to the absence of a RacGAP50C binding domain. Accordingly, we find that ectopic activation of Rho GTPase generates furrows perpendicular to the central spindle during syncytial divisions. Whereas metaphase furrow formation is myosin independent, these ectopic furrows, like conventional furrows, require myosin as well as microtubules. These studies demonstrate that early Drosophila embryogenesis is primed to form furrows at either overlapping astral microtubules or the central spindle. We propose that the shift to the latter is driven by a corresponding shift from RhoGEF2 to Pebble in controlling furrow formation.
A daily body temperature rhythm (BTR) is critical for the maintenance of homeostasis in mammals. While mammals use internal energy to regulate body temperature, ectotherms typically regulate body temperature behaviorally . Some ectotherms maintain homeostasis via a daily temperature preference rhythm (TPR) , but the underlying mechanisms are largely unknown. Here, we show that Drosophila exhibit a daily circadian clock dependent TPR that resembles mammalian BTR. Pacemaker neurons critical for locomotor activity are not necessary for TPR; instead, the dorsal neuron 2s (DN2s), whose function was previously unknown, is sufficient. This indicates that TPR, like BTR, is controlled independently from locomotor activity. Therefore, the mechanisms controlling temperature fluctuations in fly TPR and mammalian BTR may share parallel features. Taken together, our results reveal the existence of a novel DN2- based circadian neural circuit that specifically regulates TPR; thus, understanding the mechanisms of TPR will shed new light on the function and neural control of circadian rhythms.
circadian rhythm; body temperature rhythm; temperature preference; period; timeless; Drosophila
During epithelial morphogenesis, a complex comprised of the βPIX (PAK-interacting exchange factor β) and class I PAKs (p21-activated kinases) is recruited to adherens junctions. Scrib, the mammalian orthologue of the Drosophila polarity determinant and tumor suppressor Scribble, binds βPIX directly. Scrib is also targeted to adherens junctions by E-cadherin, where Scrib strengthens cadherin-mediated cell-cell adhesion. While a role for the Scrib-βPIX-PAK signaling complex in promoting membrane protrusion at wound edges has been elucidated, a function for this complex at adherens junctions remains unknown.
Here, we establish that Scrib targets βPIX and PAK2 to adherens junctions where a βPIX-PAK2 complex counterbalances apoptotic stimuli transduced by Scrib and elicited by cadherin-mediated cell-cell adhesion. Moreover, we show that this signaling pathway regulates cell survival in response to osmotic stress. Finally, we determine that in suspension cultures, the Scrib-βPIX-PAK2 complex functions to regulate anoikis elicited by cadherin engagement, with Scrib promoting and the βPIX-PAK2 complex suppressing anoikis, respectively.
Our findings demonstrate that the Scrib-βPIX-PAK2 signaling complex functions as an essential modulator of cell survival when localized to adherens junctions of polarized epithelia. The activity of this complex at adherens junctions is thereby essential for normal epithelial morphogenesis and tolerance of physiological stress. Furthermore, when localized to adherens junctions, the Scrib-βPIX-PAK2 signaling complex serves as a key determinant of anoikis sensitivity, a pivotal mechanism in tumor suppression. Thus, this work also reveals the need to expand the definition of anoikis to include a central role for adherens junctions.
Motile cells exposed to an external direct current electric field will reorient and migrate along the direction of the electric potential in a process known as galvanotaxis. The underlying physical mechanism that allows a cell to sense an electric field is unknown, although several plausible hypotheses have been proposed. In this work we evaluate the validity of each of these mechanisms.
We find that the directional motile response of fish epidermal cells to the cathode in an electric field does not require extracellular sodium or potassium, is insensitive to membrane potential, and also insensitive to perturbation of calcium, sodium, hydrogen, or chloride ion transport across the plasma membrane. Cells migrate in the direction of applied forces from laminar fluid flow, but reversal of electroosmotic flow did not affect the galvanotactic response. Galvanotaxis fails when extracellular pH is below 6, which suggests that the effective charge of membrane components may be a crucial factor. Slowing the migration of membrane components with an increase in aqueous viscosity slows the kinetics of the galvanotactic response. In addition inhibition of PI3K reverses the cell’s response to the anode, suggesting the existence of multiple signaling pathways downstream of the galvanotactic signal.
Our results are most consistent with the hypothesis that electrophoretic redistribution of membrane components of the motile cell is the primary physical mechanism for motile cells to sense an electric field. This chemical polarization of the cellular membrane is then transduced by intracellular signaling pathways canonical to chemotaxis to dictate the cell’s direction of travel.
galvanotaxis; electrotaxis; electric field; cell motility; directional cue; taxis
A dominant theme of acoustic communication is the partitioning of acoustic space into exclusive, species-specific niches to enable efficient information transfer. In insects, acoustic niche partitioning is achieved through auditory frequency filtering, brought about by the mechanical properties of their ears . The tuning of the antennal ears of mosquitoes  and flies , however, arises from active amplification, a process similar to that at work in the mammalian cochlea . Yet, the presence of active amplification in the other type of insect ears—tympanal ears—has remained uncertain . Here we demonstrate the presence of active amplification and adaptive tuning in the tympanal ear of a phylogenetically basal insect, a tree cricket. We also show that the tree cricket exploits critical oscillator-like mechanics, enabling high auditory sensitivity and tuning to conspecific songs. These findings imply that sophisticated auditory mechanisms may have appeared even earlier in the evolution of hearing and acoustic communication than currently appreciated. Our findings also raise the possibility that frequency discrimination and directional hearing in tympanal systems may rely on physiological nonlinearities, in addition to mechanical properties, effectively lifting some of the physical constraints placed on insects by their small size  and prompting an extensive reexamination of invertebrate audition.
•The tympanal ears of a tree cricket use active amplification•Active amplification and not passive resonance determines tuning to song frequency•Active amplification and tuning have an “on” and an “off” state•Crickets are the phylogenetically oldest insects with active auditory amplification
Tidal (12.4 hr) cycles of behavior and physiology adapt intertidal organisms to temporally complex coastal environments, yet their underlying mechanism is unknown. However, the very existence of an independent “circatidal” clock has been disputed, and it has been argued that tidal rhythms arise as a submultiple of a circadian clock, operating in dual oscillators whose outputs are held in antiphase i.e., ∼12.4 hr apart.
We demonstrate that the intertidal crustacean Eurydice pulchra (Leach) exhibits robust tidal cycles of swimming in parallel to circadian (24 hr) rhythms in behavioral, physiological and molecular phenotypes. Importantly, ∼12.4 hr cycles of swimming are sustained in constant conditions, they can be entrained by suitable stimuli, and they are temperature compensated, thereby meeting the three criteria that define a biological clock. Unexpectedly, tidal rhythms (like circadian rhythms) are sensitive to pharmacological inhibition of Casein kinase 1, suggesting the possibility of shared clock substrates. However, cloning the canonical circadian genes of E. pulchra to provide molecular markers of circadian timing and also reagents to disrupt it by RNAi revealed that environmental and molecular manipulations that confound circadian timing do not affect tidal timing. Thus, competent circadian timing is neither an inevitable nor necessary element of tidal timekeeping.
We demonstrate that tidal rhythms are driven by a dedicated circatidal pacemaker that is distinct from the circadian system of E. pulchra, thereby resolving a long-standing debate regarding the nature of the circatidal mechanism.
•The intertidal crustacean Eurydice pulchra exhibits circadian and tidal phenotypes•We have cloned and characterized the canonical circadian factors of Eurydice•While sensitive to CK1 inhibition, circadian and tidal clocks can be dissociated•Eurydice has a dedicated circatidal clock independent of its circadian clock
One of the defining characteristics of plant growth and morphology is the pivotal role of cell expansion. While the mechanical properties of the cell wall determine both the extent and direction of cell expansion, the cortical microtubule array plays a critical role in cell wall organization and, consequently, determining directional (anisotropic) cell expansion [1–6]. The microtubule-severing enzyme katanin is essential for plants to form aligned microtubule arrays [7–10]; however, increasing severing activity alone is not sufficient to drive microtubule alignment . Here, we demonstrate that katanin activity depends upon the behavior of the microtubule-associated protein (MAP) SPIRAL2 (SPR2). Petiole cells in the cotyledon epidermis exhibit well-aligned microtubule arrays, whereas adjacent pavement cells exhibit unaligned arrays, even though SPR2 is found at similar levels in both cell types. In pavement cells, however, SPR2 accumulates at microtubule crossover sites, where it stabilizes these crossovers and prevents severing. In contrast, in the adjacent petiole cells, SPR2 is constantly moving along the microtubules, exposing crossover sites that become substrates for severing. Consequently, our study reveals a novel mechanism whereby microtubule organization is determined by dynamics and localization of a MAP that regulates where and when microtubule severing occurs.
•SPR2 is a multifunctional MAP that is able to inhibit katanin-based MT severing•In cells with net-like microtubules, SPR2 prevents severing at microtubule crossovers•In cells with well-aligned microtubules, SPR2 mobility allows microtubule severing•SPR2 dynamics control microtubule organization by regulating microtubule severing
Class-I myosins are molecular motors that link cellular membranes to the actin cytoskeleton and play roles in membrane tension generation, membrane dynamics, and mechano-signal transduction . The widely expressed myosin-Ic (myo1c) isoform binds tightly to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) via a pleckstrin homology domain located in the myo1c tail, which is important for its proper cellular localization [2–4]. In this study, we found that myo1c can power actin motility on fluid membranes composed of physiological concentrations of PtdIns(4,5)P2, and that this motility is inhibited by high concentrations of anionic phospholipids. Strikingly, this motility occurs along curved paths in a counterclockwise direction (i.e., the actin filaments turn in leftward circles). A biotinylated myo1c construct containing only the motor domain and the lever arm anchored via streptavidin on a membrane containing biotinylated lipid can also generate asymmetric motility, suggesting the tail domain is not required for the counterclockwise turning. We found that the ability to produce counterclockwise motility is not a universal characteristic of myosin-I motors, as membrane-bound myosin-Ia (myo1a) and myosin-Ib (myo1b) are able to power actin gliding, but the actin gliding has no substantial turning bias. This work reveals a possible mechanism for establishing asymmetry in relationship to the plasma membrane.
Optogenetics is currently the state-of-the-art method for causal-oriented brain research. Despite an increasingly large number of invertebrate and rodent studies showing profound electrophysiological and behavioral effects induced by optogenetics [1,2], only two primate studies have reported modulation of local single-cell activity, but with no behavioral effects [3,4]. Here, we show that optogenetic stimulation of cortical neurons within rhesus monkey arcuate sulcus, during the execution of a visually-guided saccade task, evoked significant and reproducible changes in saccade latencies as a function of target position. Moreover, using concurrent optogenetic stimulation and functional magnetic resonance imaging (aka opto-fMRI, [5,6]) we observed optogenetically-induced changes in fMRI activity in specific functional cortical networks throughout the monkey brain. This is critical information for the advancement of optogenetic primate research models and for initiating the development of optogenetically-based cell-specific therapies with which to treat neurological diseases in humans.
Uncertainty shapes our perception of the world and the decisions we make. Two aspects of uncertainty are commonly distinguished: uncertainty in previously acquired knowledge (prior) and uncertainty in current sensory information (likelihood). Previous studies have established that humans can take both types of uncertainty into account, often in a way predicted by Bayesian statistics. However, the neural representations underlying these parameters remain poorly understood.
By varying prior and likelihood uncertainty in a decision-making task while performing neuroimaging in humans, we found that prior and likelihood uncertainty had quite distinct representations. While likelihood uncertainty activated brain regions along the early stages of the visuomotor pathway, representations of prior uncertainty were identified in specialized brain areas outside this pathway, including putamen, amygdala, insula, and orbitofrontal cortex. Furthermore, the magnitude of brain activity in the putamen predicted individuals’ personal tendencies to rely more on either prior or current information.
Our results suggest different pathways by which prior and likelihood uncertainty map onto the human brain, and provide a potential neural correlate for higher reliance on current or prior knowledge. Overall, these findings offer insights into the neural pathways that may allow humans to make decisions close to the optimal defined by a Bayesian statistical framework.
Microtubules (MTs) serve important roles in cell trafficking, division and signaling. MTs polymerize via net addition of GTP-tubulin subunits to the MT plus end, which subsequently hydrolyze to GDP-tubulin after incorporation into the MT lattice. The relatively stable GTP-tubulin subunits create a “GTP cap” at the growing MT plus end that protects the MT from catastrophe. Therefore, to understand MT assembly regulation we need to understand GTP hydrolysis reaction kinetics and the size of the GTP cap. In vitro, the GTP cap has been estimated to be as small as one layer [1-3](13 subunits) or as large as 100-200 subunits . GTP cap size estimates in vivo have not yet been reported. Using EB1-EGFP as a marker for GTP-tubulin in LLCPK1 epithelial cells, we find on average: (1) 270 EB1 dimers bound to growing MT plus ends, and (2) a GTP cap size of ~750 tubulin subunits. Thus, in vivo, the GTP cap size is far larger than previous estimates in vitro, and ~60-fold larger than a single layer cap. Consistent with these findings, we also find the tail region of a large GTP cap, 0.5-2.0 μm from the tip, promotes MT rescue and suppresses shortening. We speculate that a large GTP cap provides a locally concentrated (~100 μM) scaffold for tip-tracking proteins, and confers persistence to assembly in the face of physical barriers such as the cell cortex.
Most solid tumors are aneuploid, having a chromosome number that is not a multiple of the haploid number, and many frequently mis-segregate whole chromosomes in a phenomenon called chromosomal instability (CIN). CIN positively correlates with poor patient prognosis, indicating that reduced mitotic fidelity contributes to cancer progression by increasing genetic diversity among tumor cells. Here, we review the mechanisms underlying CIN, which include defects in chromosome cohesion, mitotic checkpoint function, centrosome copy number, kinetochore–microtubule attachment dynamics, and cell-cycle regulation. Understanding these mechanisms provides insight into the cellular consequences of CIN and reveals the possibility of exploiting CIN in cancer therapy.
The spindle assembly checkpoint (SAC) is the major surveillance system that ensures sister chromatids do not separate until all chromosomes are correctly bi-oriented during mitosis. Components of the checkpoint include Mad1, Mad2, Mad3(BubR1), Bub3 and the kinases Bub1, Mph1(Mps1) and Aurora B . Checkpoint proteins are recruited to kinetochores when individual kinetochores are not bound to spindle microtubules or not under tension [2-5]. Kinetochore association of Mad2 causes it to undergo a conformational change which promotes its association to Mad3 and Cdc20 to form the mitotic checkpoint complex (MCC). The MCC inhibits the anaphase-promoting complex/cyclosome (APC/C) until the checkpoint is satisfied. SAC silencing de-represses Cdc20-APC/C activity. This triggers the poly-ubiquitination of securin and cyclin which promotes the dissolution of sister chromatid cohesion and mitotic progression [6-8]. We, and others, recently showed that association of PP1 to the Spc7/Spc105/KNL1 family of kinetochore proteins is necessary to stabilize microtubule-kinetochore attachments and silence the SAC [9-12]. We now report that phosphorylation of the conserved MELT motifs in Spc7 by Mph1 (Mps1) recruits Bub1 and Bub3 to the kinetochore and that this is required to maintain the SAC signal.
The asymmetric polarization of cells allows specialized functions to be performed at discrete subcellular locales. Spatiotemporal coordination of polarization between groups of cells allowed the evolution of metazoa. For instance, coordinated apical-basal polarization of epithelial and endothelial cells allows transport of nutrients and metabolites across cell barriers and tissue microenvironments. The defining feature of such tissues is the presence of a central, interconnected luminal network. Although tubular networks are present in seemingly different organ systems, such as the kidney, lung, and blood vessels, common underlying principles govern their formation. Recent studies using in vivo and in vitro models of lumen formation have shed new light on the molecular networks regulating this fundamental process. We here discuss progress in understanding common design principles underpinning de novo lumen formation and expansion.
Loss-of-function mutations in TRPML1 (Transient Receptor Potential Mucolipin 1) cause a lysosomal storage disorder called mucolipidosis type IV (MLIV). Previously, we established a Drosophila model for MLIV by knocking out the single TRPML1 homolog expressed in flies . The mutant animals displayed impaired autophagy, and reduced viability during the pupal period—a phase when wild-type animals rely on autophagic sources for nutrients. However, the specific defect in autophagy has remained unclear. Here, we show that TRPML, which was localized to the membranes of late-endosomes and lysosomes in vivo, was required for fusion between late-endosomes with lysosomes. We report that loss of TRPML led to accumulation of vesicles of significantly larger volume, and loss of TRPML from the late-endosomes/lysosomes led to the accumulation of higher luminal Ca2+ within those vesicles. We also found that trpml1 mutant cells showed decreased TORC1 signaling, and a concomitant upregulation of autophagy induction. Both of these defects were reversed by activating TORC1 in the mutants genetically and by feeding the mutant larvae a high-protein diet. Feeding the larvae a high-protein diet also reduced both the pupal lethality, and the increased volume of acidic vesicles. Conversely, further inhibition of TORC1 activity by rapamycin exacerbated the mutant phenotypes. Finally, TORC1 exerted reciprocal control on TRPML function. A high amino acid diet enhanced cortical localization of TRPML, and this effect was blocked by rapamycin. Our findings delineate the interrelationship between TRPML- and TORC1-mediated nutrient sensing pathways, and also raise the intriguing possibility that amino acid supplementation might reduce the severity of the clinical manifestations associated with MLIV.
Regularities are gradually represented in cortex after extensive experience , and yet they can influence behavior after minimal exposure [2,3]. What kind of representations support such rapid statistical learning? The medial temporal lobe (MTL) can represent information from even a single experience , making it a good candidate system for assisting in initial learning about regularities. We combined anatomical segmentation of the MTL, high-resolution functional magnetic resonance imaging (fMRI), and multivariate pattern analysis (MVPA) to identify representations of objects in cortical and hippocampal areas of human MTL, assessing how these representations were shaped by exposure to regularities. Subjects viewed a continuous visual stream containing hidden temporal relationships—pairs of objects that reliably appeared nearby in time. We compared the pattern of blood oxygen level-dependent (BOLD) activity evoked by each object before and after this exposure, and found that perirhinal cortex (PRC), parahippocampal cortex (PHC), subiculum, CA1, and CA2/CA3/dentate gyrus (CA2/3/DG) encoded regularities by increasing the representational similarity of their constituent objects. Most regions exhibited bidirectional associative shaping, while CA2/3/DG represented regularities in a forward-looking predictive manner. These findings suggest that object representations in MTL come to mirror the temporal structure of the environment, supporting rapid and incidental statistical learning.
A paradigm of cytokinesis in animal cells is that the actomyosin contractile ring provides the primary force to divide the cell . In the fission yeast Schizosaccharomyces pombe, cytokinesis also involves a conserved cytokinetic ring, which has been generally assumed to provide the force for cleavage [2–4] (see also ). However, in contrast to animal cells, cytokinesis in yeast cells also requires the assembly of a cell wall septum , which grows centripetally inwards as the ring closes. Fission yeast, like other walled cells, also possess high (MPa) turgor pressure [7–9]. Here, we show that turgor pressure is an important factor in the mechanics of cytokinesis. Decreasing effective turgor pressure leads to an increase in cleavage rate, suggesting that the inward force generated by the division apparatus opposes turgor pressure. The contractile ring, which is predicted to only provide a tiny fraction of the mechanical stress required to overcome turgor, is largely dispensable for ingression; once septation has started, cleavage can continue in the absence of the contractile ring. Scaling arguments and modeling suggest that the large forces for cytokinesis are not produced by the contractile ring, but are driven by the assembly of cell wall polymers in the growing septum.
Cancer initiation, progression, and the emergence of therapeutic resistance are evolutionary phenomena of clonal somatic cell populations. Studies in microbial experimental evolution and the theoretical work inspired by such studies are yielding deep insights into the evolutionary dynamics of clonal populations, yet there has been little explicit consideration of the relevance of this rapidly growing field to cancer biology. Here, we examine how the understanding of mutation, selection, and spatial structure in clonal populations that is emerging from experimental evolution may be applicable to cancer. Along the way, we discuss some significant ways in which cancer differs from the model systems used in experimental evolution. Despite these differences, we argue that enhanced prediction and control of cancer may be possible using ideas developed in the context of experimental evolution, and we point out some prospects for future research at the interface between these traditionally separate areas.
Technological advances in biology have begun to dramatically change the way we think about evolution, development, health and disease. The ability to sequence the genomes of many individuals within a population, and across multiple species, has opened the door to the possibility of answering some long-standing and perplexing questions about our own genetic heritage. One such question revolves around the nature of cellular hyperproliferation. This cellular behavior is used to effect wound healing in most animals, as well as, in some animals, the regeneration of lost body parts. Yet at the same time, cellular hyperproliferation is the fundamental pathological condition responsible for cancers in humans. Here, I will discuss why microevolution, macroevolution and developmental biology all have to be taken into consideration when interpreting studies of both normal and malignant hyperproliferation. I will also illustrate how a synthesis of evolutionary sciences and developmental biology through the study of diverse model organisms can inform our understanding of both health and disease.
The association of inflammation with modern human diseases (e.g. obesity, cardiovascular disease, type 2 diabetes mellitus, cancer) remains an unsolved mystery of current biology and medicine. Inflammation is a protective response to noxious stimuli that unavoidably occurs at a cost to normal tissue function. This fundamental tradeoff between the cost and benefit of the inflammatory response has been optimized over evolutionary time for specific environmental conditions. Rapid change of the human environment due to niche construction outpaces genetic adaptation through natural selection, leading increasingly to a mismatch between the modern environment and selected traits. Consequently, multiple tradeoffs that affect human physiology are not optimized to the modern environment, leading to increased disease susceptibility. Here we examine the inflammatory response from an evolutionary perspective. We discuss unique aspects of the inflammatory response and its evolutionary history that can help explain the association between inflammation and modern human diseases.