Biophysical limits on athermal effects of RF and microwave radiation

Using biophysical criteria, I show that continuous radiofrequency (RF) and microwave radiation with intensity less than 10 mW/cm(2) are unlikely to affect physiology significantly through athermal mechanisms. Biological systems are fundamentally noisy on the molecular scale as a consequence of thermal agitation and are noisy macroscopically as a consequence of physiological functions and animal behavior. If electromagnetic fields are to significantly affect physiology, their direct physical effect must be greater than that from the ubiquitous endogenous noise. Using that criterion, I show that none of a set of interactions of weak fields, which I argue is nearly complete on dimensional grounds, can affect biology on the molecular scale. Moreover, I conclude that such weak fields are quite unlikely to generate significant effects in their interactions with larger biological elements such as cells. In the course of that analysis, I examine important special examples of electromagnetic interactions: "direct" interactions where biology is modified simply by the motion of charged elements generated by the electric field; resonance interactions; the effects of electrostrictive forces and induced dipole moments; and modifications of radical pair recombination probabilities. In each case, I show that it is unlikely that low intensity fields can generate significant physiological consequences.     

Native mass spectrometry: a bridge between interactomics and structural biology

Native mass spectrometry is an emerging technology that allows the topological investigation of intact protein complexes with high sensitivity and a theoretically unrestricted mass range. This unique tool provides complementary information to established technologies in structural biology, and also provides a link to high-throughput interactomics studies, which do not generate information on exact protein complex-composition, structure or dynamics. Here I review the current state of native mass spectrometry technology and discuss several important biological applications. I also describe current experimental challenges in native mass spectrometry, encouraging readers to contribute to solutions.     

Visualizing everything,everywhere, all at once: Cryo-EM and the new field of structureomics

Twenty years ago, the release of the first draft of the human genome sequence instigated a paradigm shift in genomics and molecular biology. Arguably, structural biology is entering an analogous era, with availability of an experimentally determined or predicted molecular model for almost every protein-coding gene from many genomes—producing a reference “structureome”. Structural predictions require experimental validation and not all proteins conform to a single structure, making any reference structureome necessarily incomplete. Despite these limitations, a reference structureome can be used to characterize cell state in more detail than by quantifying sequence or expression levels alone. Cryogenic electron microscopy (cryo-EM) is a method that can generate atomic resolution views of molecules and cells frozen in place. In this perspective I consider how emerging cryo-EM methods are contributing to the new field of structureomics.     

Imaging and modeling growth and morphogenesis in plants

The growth of tissues, organs or organisms derives from the coordinated activities of complex genetic regulatory networks. In addition to its molecular underpinnings, growth also generally involves significant changes in geometry. To fully understand morphogenesis in its molecular and physical contexts the development of an interdisciplinary approach is required associating biology, mathematics, and physics, which held together by computer science. Growth quantitation and digital simulations have been developed to generate and test the plausibilities of complex hypotheses. Increasingly, real-time live imaging protocols are becoming an essential part of this process. In this review, I discuss the evolution of imaging techniques in plant developmental biology and briefly examine the different ways in which these studies have shed light on growth and morphogenesis in plants.     

Plant signalling: the inexorable rise of auxin

The flow of signalling molecules across a field of cells to generate a pattern that is then transduced into a differential response in those cells is a fundamental concept in developmental biology. Recent studies have identified a system that regulates the flux of the growth factor auxin through plant tissues via the subcellular asymmetric localization of specific transporters. The recurrent use of this auxin transport system in different developmental and physiological contexts reveals a fundamental mechanism underpinning organogenesis, stem cell positioning and the growth response of the plant to the environment. Here, I will discuss key advances in the identification of auxin transporters and their integration with auxin signal transduction pathways.     

Insulin and its receptor: structure, function and evolution

I present here a personal perspective on more than three decades of research into the structural biology of the insulin-receptor interaction. The solution of the three-dimensional structure of insulin in 1969 provided a detailed understanding of the insulin surfaces involved in self-assembly. In subsequent years, hundreds of insulin analogues were prepared by insulin chemists and molecular biologists, with the goal of relating the structure to the biological function of the molecule. The design of methods for direct receptor-binding studies in the 1970s, and the cloning of the receptor in the mid 1980s, provided the required tools for detailed structure-function studies. In the absence of a full three-dimensional structure of the insulin-receptor complex, I attempt to assemble the existing pieces of the puzzle generated by our and other laboratories, in order to generate a plausible mechanistic model of the insulin-receptor interaction that explains its kinetics and negative cooperativity.     

Trafficking motifs as the basis for two-compartment signaling systems to form multiple stable states

Transport of molecules in cells is a central part of cell biology. Frequently such trafficking is not just for material transport, but also for information propagation, and serves to couple signaling circuits across cellular compartments. Here, I show that trafficking transforms simple local signaling pathways into self-organizing systems that span compartments and confer distinct states and identities to these compartments. I find that three motifs encapsulate the responses of most single-compartment signaling pathways in the context of trafficking. These motifs combine with different trafficking reactions to generate a diverse set of cellular functions. For example, trafficked bistable switches can oscillate or become quad- or tristable, depending on trafficking mechanisms and rates. Furthermore, the analysis shows how compartments participating in traffic can settle to distinct molecular compositions characteristic of distinct organelle identities. This general framework shows how the interplay between molecular movement and local reactions can generate many system functions, and give distinct identities to different parts of the cell.     

Defining the Limits of Restoration: The Need for Realistic Goals

The search for a universal statement of goals for ecological restoration continues to generate discussion and controversy. I discuss the diverse roots of restoration ecology, and show how the complex lineages within the field have led to diverse, and divergent, sets of goals. I then review the three major themes that currently are used to develop statements of goals: restoration of species, restoration of whole ecosystems or landscapes, and the restoration of ecosystem services, and point out both the advantages and the limitations and problems associated with each category. Finally, I suggest that restoration ecology would be better served by recognizing that the diversity of conditions requiring restoration demands much flexibility in goal setting, and that restorationists should seek to develop guidelines for defining the sets of conditions under which different kinds of goals are appropriate. I further suggest that goals would be more easily and more appropriately set if restorationists would set forth at the outset the true scope and limitations of what is possible in a given project. Key words: goal‐setting, wetlands, conservation biology, ecosystem management, ecosystem services, landscape management.     

Phylogenetic approaches for studying diversification

Estimating rates of speciation and extinction, and understanding how and why they vary over evolutionary time, geographical space and species groups, is a key to understanding how ecological and evolutionary processes generate biological diversity. Such inferences will increasingly benefit from phylogenetic approaches given the ever‐accelerating rates of genetic sequencing. In the last few years, models designed to understand diversification from phylogenetic data have advanced significantly. Here, I review these approaches and what they have revealed about diversification in the natural world. I focus on key distinctions between different models, and I clarify the conclusions that can be drawn from each model. I identify promising areas for future research. A major challenge ahead is to develop models that more explicitly take into account ecology, in particular the interaction of species with each other and with their environment. This will not only improve our understanding of diversification; it will also present a new perspective to the use of phylogenies in community ecology, the science of interaction networks and conservation biology, and might shift the current focus in ecology on equilibrium biodiversity theories to non‐equilibrium theories recognising the crucial role of history.     

Improved understanding of gene expression regulation using systems biology

This article reviews the current state of systems biology approaches, including the experimental tools used to generate ‘omic’ data and computational frameworks to interpret this data. Through illustrative examples, systems biology approaches to understand gene expression and gene expression regulation are discussed. Some of the challenges facing this field and the future opportunities in the systems biology era are highlighted.     

Disintegration of the ecological community

In this essay, I argue that the seemingly indestructible concept of the community as a local, interacting assemblage of species has hindered progress toward understanding species richness at local to regional scales. I suggest that the distributions of species within a region reveal more about the processes that generate diversity patterns than does the co-occurrence of species at any given point. The local community is an epiphenomenon that has relatively little explanatory power in ecology and evolutionary biology. Local coexistence cannot provide insight into the ecogeographic distributions of species within a region, from which local assemblages of species derive, nor can local communities be used to test hypotheses concerning the origin, maintenance, and regulation of species richness, either locally or regionally. Ecologists are moving toward a community concept based on interactions between populations over a continuum of spatial and temporal scales within entire regions, including the population and evolutionary processes that produce new species.     

The molecular machines that mediate microRNA maturation

MicroRNAs (miRNA) are small RNAs that regulate the translation of thousands of message RNAs and play a profound role in mammalian biology. Over the past 5 years, significant advances have been made towards understanding the pathways that generate miRNAs and the mechanisms by which miRNAs exert their regulatory functions. An emerging theme is that miRNAs are both generated by and utilized by large and complex macromolecular assemblies. Here, we review the biology of mammalian miRNAs with a focus on the macromolecular complexes that generate and control the biogenesis of miRNAs.     

Improved understanding of gene expression regulation using systems biology

This article reviews the current state of systems biology approaches, including the experimental tools used to generate 'omic' data and computational frameworks to interpret this data. Through illustrative examples, systems biology approaches to understand gene expression and gene expression regulation are discussed. Some of the challenges facing this field and the future opportunities in the systems biology era are highlighted.     

Parts and Theories in Compositional Biology

I analyze the importance of parts in the style of biological theorizing that I call compositional biology. I do this by investigating various aspects, including partitioning frames and explanatory accounts, of the theoretical perspectives that fall under and are guided by compositional biology. I ground this general examination in a comparative analysis of three different disciplines with their associated compositional theoretical perspectives: comparative morphology, functional morphology, and developmental biology. I glean data for this analysis from canonical textbooks and defend the use of such texts for the philosophy of science. I end with a discussion of the importance of recognizing formal and compositional biology as two genuinely different ways of doing biology – the differences arising more from their distinct methodologies than from scientific discipline included or natural domain studied. Ultimately, developing a translation manual between the two styles would be desirable as they currently are, at times, in conflict.     

Genetic linkage and natural selection

The prevalence of recombination in eukaryotes poses one of the most puzzling questions in biology. The most compelling general explanation is that recombination facilitates selection by breaking down the negative associations generated by random drift (i.e. Hill–Robertson interference, HRI). I classify the effects of HRI owing to: deleterious mutation, balancing selection and selective sweeps on: neutral diversity, rates of adaptation and the mutation load. These effects are mediated primarily by the density of deleterious mutations and of selective sweeps. Sequence polymorphism and divergence suggest that these rates may be high enough to cause significant interference even in genomic regions of high recombination. However, neither seems able to generate enough variance in fitness to select strongly for high rates of recombination. It is plausible that spatial and temporal fluctuations in selection generate much more fitness variance, and hence selection for recombination, than can be explained by uniformly deleterious mutations or species-wide selective sweeps.     

The levels of analysis revisited

The term levels of analysis has been used in several ways: to distinguish between ultimate and proximate levels, to categorize different kinds of research questions and to differentiate levels of reductionism. Because questions regarding ultimate function and proximate mechanisms are logically distinct, I suggest that distinguishing between these two levels is the best use of the term. Integrating across levels in research has potential risks, but many benefits. Consideration at one level can help generate novel hypotheses at the other, define categories of behaviour and set criteria that must be addressed. Taking an adaptationist stance thus strengthens research on proximate mechanisms. Similarly, it is critical for researchers studying adaptation and function to have detailed knowledge of proximate mechanisms that may constrain or modulate evolutionary processes. Despite the benefits of integrating across ultimate and proximate levels, failure to clearly identify levels of analysis, and whether or not hypotheses are exclusive alternatives, can create false debates. Such non-alternative hypotheses may occur between or within levels, and are not limited to integrative approaches. In this review, I survey different uses of the term levels of analysis and the benefits of integration, and highlight examples of false debate within and between levels. The best integrative biology reciprocally uses ultimate and proximate hypotheses to generate a more complete understanding of behaviour.     

The concept of mechanism in biology

The concept of mechanism in biology has three distinct meanings. It may refer to a philosophical thesis about the nature of life and biology ('mechanicism'), to the internal workings of a machine-like structure ('machine mechanism'), or to the causal explanation of a particular phenomenon ('causal mechanism'). In this paper I trace the conceptual evolution of 'mechanism' in the history of biology, and I examine how the three meanings of this term have come to be featured in the philosophy of biology, situating the new 'mechanismic program' in this context. I argue that the leading advocates of the mechanismic program (i.e., Craver, Darden, Bechtel, etc.) inadvertently conflate the different senses of 'mechanism'. Specifically, they all inappropriately endow causal mechanisms with the ontic status of machine mechanisms, and this invariably results in problematic accounts of the role played by mechanism-talk in scientific practice. I suggest that for effective analyses of the concept of mechanism, causal mechanisms need to be distinguished from machine mechanisms, and the new mechanismic program in the philosophy of biology needs to be demarcated from the traditional concerns of mechanistic biology.     

Alleles versus mutations: Understanding the evolution of genetic architecture requires a molecular perspective on allelic origins

Perspectives on the role of large‐effect quantitative trait loci (QTL) in the evolution of complex traits have shifted back and forth over the past few decades. Different sets of studies have produced contradictory insights on the evolution of genetic architecture. I argue that much of the confusion results from a failure to distinguish mutational and allelic effects, a limitation of using the Fisherian model of adaptive evolution as the lens through which the evolution of adaptive variation is examined. A molecular‐based perspective reveals that allelic differences can involve the cumulative effects of many mutations plus intragenic recombination, a model that is supported by extensive empirical evidence. I discuss how different selection regimes could produce very different architectures of allelic effects under a molecular‐based model, which may explain conflicting insights on genetic architecture from studies of variation within populations versus between divergently selected populations. I address shortcomings of genome‐wide association study (GWAS) practices in light of more suitable models of allelic evolution, and suggest alternate GWAS strategies to generate more valid inferences about genetic architecture. Finally, I discuss how adopting more suitable models of allelic evolution could help redirect research on complex trait evolution toward addressing more meaningful questions in evolutionary biology.