Scientific discovery as a combinatorial optimisation problem: How best to navigate the landscape of possible experiments?

A considerable number of areas of bioscience, including gene and drug discovery, metabolic engineering for the biotechnological improvement of organisms, and the processes of natural and directed evolution, are best viewed in terms of a 'landscape' representing a large search space of possible solutions or experiments populated by a considerably smaller number of actual solutions that then emerge. This is what makes these problems 'hard', but as such these are to be seen as combinatorial optimisation problems that are best attacked by heuristic methods known from that field. Such landscapes, which may also represent or include multiple objectives, are effectively modelled in silico, with modern active learning algorithms such as those based on Darwinian evolution providing guidance, using existing knowledge, as to what is the 'best' experiment to do next. An awareness, and the application, of these methods can thereby enhance the scientific discovery process considerably. This analysis fits comfortably with an emerging epistemology that sees scientific reasoning, the search for solutions, and scientific discovery as Bayesian processes.     

Automated and dynamic abstraction of MPI application performance

Developing an efficient parallel application is not an easy task, and achieving a good performance requires a thorough understanding of the program’s behavior. Careful performance analysis and optimization are crucial. To help developers or users of these applications to analyze the program’s behavior, it is necessary to provide them with an abstraction of the application performance. In this paper, we propose a dynamic performance abstraction technique, which enables the automated discovery of causal execution paths, composed of communication and computational activities, in MPI parallel programs. This approach enables autonomous and low-overhead execution monitoring that generates performance knowledge about application behavior for the purpose of online performance diagnosis. Our performance abstraction technique reflects an application behavior and is made up of elements correlated with high-level program structures, such as loops and communication operations. Moreover, it characterizes all elements with statistical execution profiles. We have evaluated our approach on a variety of scientific parallel applications. In all scenarios, our online performance abstraction technique proved effective for low-overhead capturing of the program’s behavior and facilitated performance understanding.     

PROTERAN: animated terrain evolution for visual analysis of patterns in protein folding trajectory

The mechanism of protein folding remains largely a mystery in molecular biology, despite the enormous effort from many groups in the past decades. Currently, the protein folding mechanism is often characterized by calculating the free energy landscape versus various reaction coordinates such as the fraction of native contacts, the radius of gyration and so on. In this paper, we present an integrated approach towards understanding the folding process via visual analysis of patterns of these reaction coordinates. The three disparate processes (1) protein folding simulation, (2) pattern elicitation and (3) visualization of patterns, work in tandem. Thus as the protein folds, the changing landscape in the pattern space can be viewed via the visualization tool, PROTERAN, a program we developed for this purpose. We first present an incremental (on-line) trie-based pattern discovery algorithm to elicit the patterns and then describe the terrain metaphor based visualization tool. Using two example small proteins, a beta-hairpin and a designed protein Trp-cage, we next demonstrate that this combined pattern discovery and visualization approach extracts crucial information about protein folding intermediates and mechanism.     

The Bio-semiotic Roots of Metapsychology

This paper provides an overview of the origins, vicissitudes, and abandonment of ‘metapsychology’, the psycho-biological scientific core of the Freudian opus, and introduces the authors’ key revisions. Although couched in the language of metaphor and analogy from 19th century physics, the conceptual foundations of Freud’s theories contained the seeds of a bio-semiotic theory of mind and of human nature in the natural world. Its updated, modernized, version opens the door to an inter-penetrative epistemology leading to universal principles of logical form, applicable to all types of vital inter-action.     

Using a classic paper by Gottschalk and Mylle to teach the countercurrent model of urinary concentration

Most undergraduates lack the scientific background to read and appreciate much of the primary literature in physiology. Even when the underlying concepts are elegantly simple, the inherent complexity of contemporary papers often makes the work inaccessible to them. However, with a little help, they can be guided to an understanding of the creative thought processes that underlie the research and to appreciate its significance. This is especially true of many classic papers in physiology that often rely on easily comprehensible techniques. Moreover, the American Physiological Society (APS) has invited prominent scientists to select important papers in their fields and to write essays that both put the work into historical context and explain why it is scientifically important. The APS Legacy Project makes these classic papers freely available online. One such paper by Gottschalk and Mylle presents data from a series of micropuncture studies that confirm all of the predictions of the countercurrent exchange model of concentrated urine production (2). The included handout of questions for discovery learning and teaching points suggest ways to use the paper as an instructional resource.     

Integration of ethnobotany and phytochemistry. dream or reality?

The major challenge of this paper comprises an attempt to compare the wealth of folk-information based on "traditional knowledge" with the efficacy of a chemo-biological background based on scientific knowledge. Surprisingly, correlations between plant uses (as food and medicine) and evolutionary status according to morphology (as assigned by Sporne indices) and metabolism (as assigned by diversity of phytochemicals) obey strikingly uniform systematic and evolutionary trends. The resulting patterns suggest a dynamic chemical mechanism for the bioactivity in plants regulated by the antagonistic gallate/caffeate pair. This finding is an important step toward the construction of a coherent chemo-biological language by a dynamic holistic quantitative methodology, one of the most potent prospects for understanding the functioning of nature.     

Styles of scientific reasoning: Adolf Remane (1898–1976) and the German evolutionary synthesis

Adolf Remane is widely considered to have been one of the most influential German zoologists of the 20th Century, yet Ernst Mayr persistently characterized him as an idealistic morphologist, that is, a typologist unable to understand population genetics or indeed Darwinian theory. This stands in sharp contrast to Mayr's praise for Bernhard Rensch as one of the most important German contributors to the Modern Synthesis of evolutionary theory. Remane's style of scientific reasoning is analysed in his writings on microsystematics, ecology, comparative morphology and phylogenetics and found to be highly consistent throughout these varied fields of research, while differing fundamentally from the eminently statistical foundations of both population genetics and natural selection theory that were embraced by Mayr. A comparative analysis of Rensch's understanding of science in general, and biology in particular, shows him to share core values with Remane, both authors rooted in the Mandarin tradition of the German professoriate. Biographical and socio‐political factors appear to have influenced Mayr's contrasting perception of Remane and Rensch, one that would influence later biologists and historians of science.     

Observation and cogitation: how serendipity provides the building blocks of scientific discovery

The identification of serendipitous findings in field-based animal research is challenging in part because investigators are reluctant to declare a discovery accidental. Investigators recognize that many factors must be considered. For example, the impact of using carefully ordered observational search patterns in ecologic, pathologic, and epidemiologic investigations could result in findings being categorized as "sought" versus "unsought." Team collaborations are common in these types of investigations and have advantages related to the application of multiple paradigms, paradigm mixing, and paradigm shifting. This approach reduces the perception of serendipity. Issues of search image refinement and the co-discovery of sought and unsought discoveries additionally cloud the identification of a truly serendipitous finding. Nevertheless, basic curiosity and observation are necessary precursors to scientific discovery. It should be recognized that serendipitous discoveries are of significant value in the advancement of science and often present the foundation for important intellectual leaps of understanding.     

A neural network model of metaphor understanding with dynamic interaction based on a statistical language analysis: targeting a human-like model

The purpose of this paper is to construct a model that represents the human process of understanding metaphors, focusing specifically on similes of the form an "A like B". Generally speaking, human beings are able to generate and understand many sorts of metaphors. This study constructs the model based on a probabilistic knowledge structure for concepts which is computed from a statistical analysis of a large-scale corpus. Consequently, this model is able to cover the many kinds of metaphors that human beings can generate. Moreover, the model implements the dynamic process of metaphor understanding by using a neural network with dynamic interactions. Finally, the validity of the model is confirmed by comparing model simulations with the results from a psychological experiment.     

iBiology: communicating the process of science

The Internet hosts an abundance of science video resources aimed at communicating scientific knowledge, including webinars, massive open online courses, and TED talks. Although these videos are efficient at disseminating information for diverse types of users, they often do not demonstrate the process of doing science, the excitement of scientific discovery, or how new scientific knowledge is developed. iBiology (www.ibiology.org), a project that creates open-access science videos about biology research and science-related topics, seeks to fill this need by producing videos by science leaders that make their ideas, stories, and experiences available to anyone with an Internet connection.     

Serendipity and new drugs for infectious disease

Serendipity, in various shades of semantic legitimacy, is abundantly evident in the history of the chemotherapy of infectious disease. We may be on the threshold of a new era of rational drug design, but most medications for infectious diseases have arisen, and continue to arise, from chance observation, clinical experience, and the empirical search for substances active against pathogens. Chance does not produce drugs; but where chance has played a pivotal role in drug discovery, the event may be considered serendipitous to a greater or lesser degree. In a deliberate search for new drugs, it is often difficult to assess the degree to which any resulting discovery is serendipitous, and the usefulness of the term becomes debatable. Many therapeutic advances emerge from research involving animals, and a triggering "happy accident" may reside in the most basic aspects of animal care or in the most arcane knowledge of animals. The examples discussed in this article deal mostly with parasitic disease and the use of animal models in the discovery of antiparasitic agents. In this area, as in others, chance has laid the groundwork for scientific advancement and practical benefit. Although the applicability of the word serendipity to drug discovery may often be uncertain, the role played by chance should be recognized and welcomed.     

A biological framework for understanding farmers’ plant breeding

We present a framework for understanding farmer plant breeding (including both choice of varieties and populations and plant selection) in terms of the basic biological model of scientific plant breeding, focusing on three key components of that model: 1) genetic variation, 2) environmental variation and variation of genotype-by-environment interaction, and 3) plant selection. For each of these concepts we suggest questions for research on farmers’plant breeding (farmers’ knowledge, practice, and crop varieties and growing environments). A sample of recent research shows a range of explicit and implicit answers to these questions which are often contradictory, suggesting that generalizations based on experience with specific varieties, environments or farmers may not be valid. They also suggest that farmers’ practice reflects an understanding of their crop varieties and populations that is in many ways fundamentally similar to that of plant breeders; yet, is also different, in part because the details of their experiences are different. Further research based on this framework should be valuable for participatory or collaborative plant breeding that is currently being proposed to reunite farmer and scientific plant breeding.     

Science,industry and the laity: Towards a knowledgeable society for biotechnology

This paper is concerned with the task of developing a 'knowledgeable society' for biotechnology. This is hindered by the fact that the scientific and commercial communities often engage in separate discourses from that which engages the general public. Different concepts of knowledge ('knowing') and learning underpin preoccupations and concerns in these three spheres, and different logics and assumptions about knowledge often apply. The paper begins by highlighting the key issues that exercise people in the public domain, and in relation to science and industry. It then applies concepts of knowledge, communication and learning to show how people in these domains construct issues differently. Finally, it makes some predictions and suggestions for how a more knowledgeable society may evolve.     

Preclinical safety testing of biotechnology-derived pharmaceuticals

The unique and complex nature of biotechnology-derived pharmaceuticals has meant that it is often not possible to follow the conventional safety testing programs used for chemicals, and hence they are evaluated on a case-by-case basis. Nonclinical safety testing programs must be rationally designed with a strong scientific understanding of the product, including its method of manufacture, purity, sequence, structure, species specificity, pharmacological and immunological effects, and intended clinical use. This knowledge, coupled with a firm understanding of the regulatory requirements for particular product types, will ensure that the most sensitive and regulatory-compliant test systems are used to optimize the chances of gaining regulatory approval for clinical testing or marketing authorization in the shortest possible time frame.     

"Meaning-making" in language and biology

The linguistic metaphor in biology adheres to a representational theory that seeks similarities between pre-given domains. The point of departure of this paper is the generative and nonrepresentational conception of metaphor. This paper argues that by adopting the nonrepresentational conception of metaphor, meaning-making may be the appropriate perspective for understanding biological systems. In both cases (the linguistic and the biological), boundary conditions between different levels of organization use micro-level disorganization to create macro-level organization.     

Genomics: shifts in metaphorical landscape between 2000 and 2003

This article examines the shifts and changes in the metaphors used to describe the human genome and the human genome project (HGP) between 2000 and 2003, with the year 2001 as a trigger for genomic and metaphorical reflection. We want to answer questions, such as: Did the findings announced in 2001 shake the metaphorical foundations on which the HGP had been built or not? Did novel metaphors capture the imagination of scientists and the public or did old metaphors survive throughout this period? What influence does the continuity or discontinuity in metaphorical framing of the HGP have on the public perception of the HGP as well as on its scientific understanding? To answer these questions we have systematically compared the metaphors used in one major scientific journal, Nature, and in one major UK newspaper, the online edition of the Guardian/The Observer during a period of two months around June 2000, February 2001 and April 2003.     

The concept of specificity and the Italian contribution to the discovery of the malaria transmission cycle

At the dawn of the 20th century, the change in the scientific, political and cultural attitudes towards malaria was the result of the discovery of the theoretical simplicity of the malaria transmission cycle and of the possibility to interrupt it, by avoiding the contacts between people and mosquitoes. The 'mosquito hypothesis', suggested already in the 1880s, had to be included into a coherent scientific theory, in which a fundamental part was played by the concept of specificity. The paper analyses the Italian contribution to this scientific change and the epistemological aspects of the debate between Ronald Ross and Battista Grassi about their respective role in the discovery of the human malaria transmission cycle. This debate has been often interpreted in sociological or psychological terms. However, behind the dispute there is a different definition of what is a scientific explanation in biological sciences and in particular in parasitology. This point is made clear by the analysis of four different theoretical problems implied in the discovery of the transmission cycle: the concept of specificity, the comparative method in parasitology, the specificity of the life-cycle of parasites and vectors, and the role of the analogical reasoning in science and medicine.     

On the Epistemological Crisis in Genomics

There is an epistemological crisis in genomics. At issue is what constitutes scientific knowledge in genomic science, or systems biology in general. Does this crisis require a new perspective on knowledge heretofore absent from science or is it merely a matter of interpreting new scientific developments in an existing epistemological framework? This paper discusses the manner in which the experimental method, as developed and understood over recent centuries, leads naturally to a scientific epistemology grounded in an experimental-mathematical duality. It places genomics into this epistemological framework and examines the current situation in genomics. Meaning and the constitution of scientific knowledge are key concerns for genomics, and the nature of the epistemological crisis in genomics depends on how these are understood.     

Entitymetrics: Measuring the Impact of Entities

This paper proposes entitymetrics to measure the impact of knowledge units. Entitymetrics highlight the importance of entities embedded in scientific literature for further knowledge discovery. In this paper, we use Metformin, a drug for diabetes, as an example to form an entity-entity citation network based on literature related to Metformin. We then calculate the network features and compare the centrality ranks of biological entities with results from Comparative Toxicogenomics Database (CTD). The comparison demonstrates the usefulness of entitymetrics to detect most of the outstanding interactions manually curated in CTD.