The concept of balance in microbiome research.

Microbiome research is changing how ecosystems, including animal bodies, are understood. In the case of humans, microbiome knowledge is transforming medical approaches and applications. However, the field is still young, and many conceptual and explanatory issues need resolving. These include how microbiome causality is understood, and how to conceptualize the role microbiomes have in the health status of their hosts and other ecosystems. A key concept that crops up in the medical microbiome literature is "balance." A balanced microbiome is thought to produce health and an imbalanced one disease. Based on a quantitative and qualitative analysis of how balance is used in the microbiome literature, this "think again" essay critically analyses each of the several subconceptions of balance. As well as identifying problems with these uses, the essay suggests some starting points for filling this conceptual gap in microbiome research.

Philosophies of funding.

Successful scientific practice encompasses broader and more varied modes of investigation than can be captured by focusing on hypothesis-driven research. We examine the emphases that major US and UK funding agencies place on particular modes of research practice and suggest that funding agency guidelines should be informed by a more dynamic and multidimensional account of scientific practice.

On Drugs.

Despite their centrality to medicine, drugs are not easily defined. We introduce two desiderata for a basic definition of medical drugs. It should: (a) capture everything considered to be a drug in medical contexts and (b) rule out anything that is not considered to be a drug. After canvassing a range of options, we find that no single definition of drugs can satisfy both desiderata. We conclude with three responses to our exploration of the drug concept: maintain a monistic concept, or choose one of two pluralistic outcomes. Notably, the distinction between drugs and other substances is placed under pressure by the most plausible of the options available.

Contrasting Strategies: Human Eukaryotic Versus Bacterial Microbiome Research.

Most discussions of human microbiome research have focused on bacterial investigations and findings. Our target is to understand how human eukaryotic microbiome research is developing, its potential distinctiveness, and how problems can be addressed. We start with an overview of the entire eukaryotic microbiome literature (578 papers), show tendencies in the human-based microbiome literature, and then compare the eukaryotic field to more developed human bacterial microbiome research. We are particularly concerned with problems of interpretation that are already apparent in human bacterial microbiome research (e.g. disease causality, probiotic interventions, evolutionary claims). We show where each field converges and diverges, and what this might mean for progress in human eukaryotic microbiome research. Our analysis then makes constructive suggestions for the future of the field.

Metabolic and microbial perspectives on the "evolution of evolution".

Identifying and theorizing major turning points in the history of life generates insights into not only world-changing evolutionary events but also the processes that bring these events about. In his treatment of these issues, Bonner identifies the evolution of sex, multicellularity, and nervous systems as enabling the "evolution of evolution," which involves fundamental transformations in how evolution occurs. By contextualizing his framework within two decades of theorizing about major transitions in evolution, we identify some basic problems that Bonner's theory shares with much of the prevailing literature. These problems include implicit progressivism, theoretical disunity, and a limited ability to explain major evolutionary transformations. We go on to identify events and processes that are neglected by existing views. In contrast with the "vertical" focus on replication, hierarchy, and morphology that preoccupies most of the literature on major transitions, we propose a "horizontal" dimension in which metabolism and microbial innovations play a central explanatory role in understanding the broad-scale organization of life.

Endosymbiosis and its implications for evolutionary theory.

Historically, conceptualizations of symbiosis and endosymbiosis have been pitted against Darwinian or neo-Darwinian evolutionary theory. In more recent times, Lynn Margulis has argued vigorously along these lines. However, there are only shallow grounds for finding Darwinian concepts or population genetic theory incompatible with endosymbiosis. But is population genetics sufficiently explanatory of endosymbiosis and its role in evolution? Population genetics "follows" genes, is replication-centric, and is concerned with vertically consistent genetic lineages. It may also have explanatory limitations with regard to macroevolution. Even so, asking whether population genetics explains endosymbiosis may have the question the wrong way around. We should instead be asking how explanatory of evolution endosymbiosis is, and exactly which features of evolution it might be explaining. This paper will discuss how metabolic innovations associated with endosymbioses can drive evolution and thus provide an explanatory account of important episodes in the history of life. Metabolic explanations are both proximate and ultimate, in the same way genetic explanations are. Endosymbioses, therefore, point evolutionary biology toward an important dimension of evolutionary explanation.

Microbiota-gut-brain research: A critical analysis.

Microbiota-gut-brain (MGB) research is a fast-growing field of inquiry with important implications for how human brain function and behaviour are understood. Researchers manipulate gut microbes ("microbiota") to reveal connections between intestinal microbiota and normal brain functions (e.g., cognition, emotion, and memory) or pathological states (e.g., anxiety, mood disorders, and neural developmental disorders such as autism). Many claims are made about causal relationships between gut microbiota and human behaviour. By uncovering these relationships, MGB research aims to offer new explanations of mental health and potential avenues of treatment.So far, limited evaluation has been made of MGB's methods and its core experimental findings, many of which are extensively reiterated in copious reviews of the field. These factors, plus the self-help potential of MGB, have combined to encourage uncritical public uptake of MGB discoveries. Both social and professional media focus on the potential for dietary intervention in mental health, and causal relationships are assumed to be established.Our target article has two main aims. One is to examine critically the core practices and findings of experimental MGB research and to raise questions about them for brain and behavioural scientists who may not be familiar with the field. The other is to challenge the way in which MGB findings are presented. Our positive goal is to suggest how current problems and weaknesses may be addressed, in order for both scientific and public audiences to gain a clearer picture of MGB research and its strengths and limitations.

The Experimental Study of Bacterial Evolution and Its Implications for the Modern Synthesis of Evolutionary Biology.

Since the 1940s, microbiologists, biochemists and population geneticists have experimented with the genetic mechanisms of microorganisms in order to investigate evolutionary processes. These evolutionary studies of bacteria and other microorganisms gained some recognition from the standard-bearers of the modern synthesis of evolutionary biology, especially Theodosius Dobzhansky and Ledyard Stebbins. A further period of post-synthesis bacterial evolutionary research occurred between the 1950s and 1980s. These experimental analyses focused on the evolution of population and genetic structure, the adaptive gain of new functions, and the evolutionary consequences of competition dynamics. This large body of research aimed to make evolutionary theory testable and predictive, by giving it mechanistic underpinnings. Although evolutionary microbiologists promoted bacterial experiments as methodologically advantageous and a source of general insight into evolution, they also acknowledged the biological differences of bacteria. My historical overview concludes with reflections on what bacterial evolutionary research achieved in this period, and its implications for the still-developing modern synthesis.

Microbes, mathematics, and models.

Microbial model systems have a long history of fruitful use in fields that include evolution and ecology. In order to develop further insight into modelling practice, we examine how the competitive exclusion and coexistence of competing species have been modelled mathematically and materially over the course of a long research history. In particular, we investigate how microbial models of these dynamics interact with mathematical or computational models of the same phenomena. Our cases illuminate the ways in which microbial systems and equations work as models, and what happens when they generate inconsistent findings about shared targets. We reveal an iterative strategy of comparative modelling in different media, and suggest reasons why microbial models have a special degree of epistemic tractability in multimodel inquiry.

From endosymbiosis to holobionts: Evaluating a conceptual legacy.

In her influential 1967 paper, Lynn Margulis synthesized a range of data to support the idea of endosymbiosis. Building on the success of this work, she applied the same methodology to promote the role of symbiosis more generally in evolution. As part of this broader project, she coined the term 'holobiont' to refer to a unified entity of symbiont and host. This concept is now applied with great gusto in microbiome research, and often implies not just a physiological unit but also various senses of an evolving system. My analysis will track how Margulis came to propose the term, its current use in microbiome research, and how those applications link back to Margulis. I then evaluate what contemporary use says about Margulis's legacy for microbiome research.

Histories of molecules: Reconciling the past.

Molecular data and methods have become centrally important to evolutionary analysis, largely because they have enabled global phylogenetic reconstructions of the relationships between organisms in the tree of life. Often, however, molecular stories conflict dramatically with morphology-based histories of lineages. The evolutionary origin of animal groups provides one such case. In other instances, different molecular analyses have so far proved irreconcilable. The ancient and major divergence of eukaryotes from prokaryotic ancestors is an example of this sort of problem. Efforts to overcome these conflicts highlight the role models play in phylogenetic reconstruction. One crucial model is the molecular clock; another is that of 'simple-to-complex' modification. I will examine animal and eukaryote evolution against a backdrop of increasing methodological sophistication in molecular phylogeny, and conclude with some reflections on the nature of historical science in the molecular era of phylogeny.

Evolutionary systems biology: what it is and why it matters.

Evolutionary systems biology (ESB) is a rapidly growing integrative approach that has the core aim of generating mechanistic and evolutionary understanding of genotype-phenotype relationships at multiple levels. ESB's more specific objectives include extending knowledge gained from model organisms to non-model organisms, predicting the effects of mutations, and defining the core network structures and dynamics that have evolved to cause particular intracellular and intercellular responses. By combining mathematical, molecular, and cellular approaches to evolution, ESB adds new insights and methods to the modern evolutionary synthesis, and offers ways in which to enhance its explanatory and predictive capacities. This combination of prediction and explanation marks ESB out as a research manifesto that goes further than its two contributing fields. Here, we summarize ESB via an analysis of characteristic research examples and exploratory questions, while also making a case for why these integrative efforts are worth pursuing.

When integration fails: Prokaryote phylogeny and the tree of life.

Much is being written these days about integration, its desirability and even its necessity when complex research problems are to be addressed. Seldom, however, do we hear much about the failure of such efforts. Because integration is an ongoing activity rather than a final achievement, and because today's literature about integration consists mostly of manifesto statements rather than precise descriptions, an examination of unsuccessful integration could be illuminating to understand better how it works. This paper will examine the case of prokaryote phylogeny and its apparent failure to achieve integration within broader tree-of-life accounts of evolutionary history (often called 'universal phylogeny'). Despite the fact that integrated databases exist of molecules pertinent to the phylogenetic reconstruction of all lineages of life, and even though the same methods can be used to construct phylogenies wherever the organisms fall on the tree of life, prokaryote phylogeny remains at best only partly integrated within tree-of-life efforts. I will examine why integration does not occur, compare it with integrative practices in animal and other eukaryote phylogeny, and reflect on whether there might be different expectations of what integration should achieve. Finally, I will draw some general conclusions about integration and its function as a 'meta-heuristic' in the normative commitments guiding scientific practice.

Evolutionary systems biology: historical and philosophical perspectives on an emerging synthesis.

Systems biology (SB) is at least a decade old now and maturing rapidly. A more recent field, evolutionary systems biology (ESB), is in the process of further developing system-level approaches through the expansion of their explanatory and potentially predictive scope. This chapter will outline the varieties of ESB existing today by tracing the diverse roots and fusions that make up this integrative project. My approach is philosophical and historical. As well as examining the recent origins of ESB, I will reflect on its central features and the different clusters of research it comprises. In its broadest interpretation, ESB consists of five overlapping approaches: comparative and correlational ESB; network architecture ESB; network property ESB; population genetics ESB; and finally, standard evolutionary questions answered with SB methods. After outlining each approach with examples, I will examine some strong general claims about ESB, particularly that it can be viewed as the next step toward a fuller modern synthesis of evolutionary biology (EB), and that it is also the way forward for evolutionary and systems medicine. I will conclude with a discussion of whether the emerging field of ESB has the capacity to combine an even broader scope of research aims and efforts than it presently does.

Rethinking microbial infallibility in the metagenomics era.

The 'principle of microbial infallibility' was a mainstay of microbial physiology and environmental microbiology in earlier decades. This principle asserts that wherever there is an energetic gain to be made from environmental resources, microorganisms will find a way to take advantage of the situation. Although previously disputed, this claim was revived with the discovery of anammox bacteria and other major contributors to biogeochemistry. Here, we discuss the historical background to microbial infallibility, and focus on its contemporary relevance to metagenomics. Our analysis distinguishes exploration-driven metagenomics from hypothesis-driven metagenomics. In particular, we show how hypothesis-driven metagenomics can use background assumptions of microbial infallibility to enable the formulation of hypotheses to be tested by enrichment cultures. Discoveries of comammox and the anaerobic oxidation of methane are major instances of such strategies, and we supplement them with outlines of additional examples. This overview highlights one way in which metagenomics is making the transition from an exploratory data-analysis programme of research to a hypothesis-testing one. We conclude with a discussion of how microbial infallibility is a heuristic with far-reaching implications for the investigation of life.

Concepts of the last eukaryotic common ancestor.

Insight into the last eukaryotic common ancestor (LECA) is central to any phylogeny-based reconstruction of early eukaryotic evolution. Increasing amounts of data enable such reconstructions, without necessarily providing further insight into what LECA actually was. We consider four possible concepts of LECA: an abstract phylogenetic state, a single cell, a population, and a consortium of organisms. We argue that the view most realistically underlying work in the field is that of LECA as a population. Drawing on recent findings of genomically heterogeneous populations in eukaryotes ('pangenomes'), we examine the evolutionary implications of a pangenomic LECA population. For instance, how does this concept affect standard expectations about the ecology, geography, fitness, and diversification of LECA? Does it affect evolutionary interpretations of LECA's cellular functions? Finally, we examine whether this novel pangenomic concept of LECA has implications for phylogenetic reconstructions of early eukaryote evolution. Our aim is to add to the conceptual toolkit for developing theories of LECA and interpreting genomic datasets.

'Everything is everywhere: but the environment selects': ubiquitous distribution and ecological determinism in microbial biogeography.

Recent discoveries of geographical patterns in microbial distribution are undermining microbiology's exclusively ecological explanations of biogeography and their fundamental assumption that 'everything is everywhere: but the environment selects'. This statement was generally promulgated by Dutch microbiologist Martinus Wilhelm Beijerinck early in the twentieth century and specifically articulated in 1934 by his compatriot, Lourens G. M. Baas Becking. The persistence of this precept throughout twentieth-century microbiology raises a number of issues in relation to its formulation and widespread acceptance. This paper will trace the conceptual history of Beijerinck's claim that 'everything is everywhere' in relation to a more general account of its theoretical, experimental and institutional context. His principle also needs to be situated in relationship to plant and animal biogeography, which, this paper will argue, forms a continuum of thought with microbial biogeography. Finally, a brief overview of the contemporary microbiological research challenging 'everything is everywhere' reveals that philosophical issues from Beijerinck's era of microbiology still provoke intense discussion in twenty-first century investigations of microbial biogeography.

The study of socioethical issues in systems biology.

Systems biology is the rapidly growing and heavily funded successor science to genomics. Its mission is to integrate extensive bodies of molecular data into a detailed mathematical understanding of all life processes, with an ultimate view to their prediction and control. Despite its high profile and widespread practice, there has so far been almost no bioethical attention paid to systems biology and its potential social consequences. We outline some of systems biology's most important socioethical issues by contrasting the concept of systems as dynamic processes against the common static interpretation of genomes. New issues arise around systems biology's capacities for in silico testing, changing cultural understandings of life, synthetic biology, and commercialization. We advocate an interdisciplinary and interactive approach that integrates social and philosophical analysis and engages closely with the science. Overall, we argue that systems biology socioethics could stimulate new ways of thinking about socioethical studies of life sciences.