The discovery and ongoing investigation of microRNAs suggest important conceptual and methodological lessons for philosophers and historians of biology. This paper provides an account of miRNA research and the shift from viewing these tiny regulatory entities as minor curiosities to seeing them as major players in the post-transcriptional regulation of genes. Conceptually, the study of miRNAs is part of a broader change in understandings of genetic regulation, in which simple switch-like mechanisms were reinterpreted as aspects of complex cellular and genome-wide (...) processes. Among them are the activities of small RNAs, previously regarded as non-functional. Methodologically, the miRNA story suggests new ways of characterizing biological research that should prove helpful to philosophers of science who seek to develop more pluralistic, pragmatic models of scientific inquiry. miRNA research displays iterative movements between multiple modes of investigation that include not only the proposal and testing of hypotheses but also exploratory, technology-oriented and question-driven modes of research. As an exemplary story of scientific discovery and development, the miRNA case illustrates transitions from genetics to genomics and systems biology, and it shows how diverse configurations of research practice are related to major scientific advances. (shrink)

In 1971, Günter Blobel and David Sabatini proposed a novel and quite speculative schematic model to describe how proteins might reach the proper cellular location. According to their proposal, proteins destined to be secreted from the cell contain a “signal” to direct their release. Despite the fact that Blobel and Sabatini presented their signal hypothesis as a “beautiful idea” not grounded in experimental evidence, they received criticism from other scientists who opposed such speculation. Following the publication of the 1971 model, (...) Blobel persisted in conducting experiments and revising the model to incorporate new data. In fact, over the period of 1975–1984, Blobel and colleagues published five subsequent schematic models of the signal hypothesis, each revised based on new laboratory evidence. I propose that the original 1971 model can be viewed as an epistemic creation. Additionally, analysis of the subsequent schematic diagrams over the period of 1975–1984 allows one to track Blobel’s changing conception of an epistemic object over time. Furthermore, the entire series of schematic diagrams presented by Blobel from 1971 to 1984 allow one to visualize the initial conception and subsequent reworking of a scientific theory. In 1999, Blobel was awarded the Nobel Prize in Physiology or Medicine for his work on the signal hypothesis, which was ultimately supported by experimental evidence gathered after the speculative model was published. (shrink)

The history of biochemistry and molecular biology is replete with examples of erroneous theories that persisted for considerable lengths of time before they were rejected. This paper examines patterns of dissolution of three such erroneous hypotheses: The idea that nucleic acids are tetrads of the four nucleobases (‘the tetranucleotide hypothesis’); the notion that proteins are collinear with their encoding genes in all branches of life; and the hypothesis that proteins are synthesized by reverse action of proteolytic enzymes. Analysis of these (...) cases indicates that amassed contradictory empirical findings did not prompt critical experimental testing of the prevailing theories nor did they elicit alternative hypotheses. Rather, the incorrect models collapsed when experiments that were not purposely designed to test their validity exposed new facts. (shrink)

The first part of this paper has shown that the development of regulatory genetics and the lactose operon model stemmed from laboratory cultures rooted in local traditions. A "physiological" culture may be recognized in the Pasteurian context. The institutional continuity provided the basis for a tenuous link between Pasteur, Lwoff, and Monod. My claim is that the "national" value of regulatory and physiological genetics is an artifact produced in the course of the legitimization process accompanying the institutionalisation of the discipline. (...) In the 1960s, the lactose operon model was turned into a "flag-object," a symbol of the new culture. The work done by the Pasteurian group became therefore the most important, if not the only, exemplar of molecular biology in France.The second part o f the paper described the origins of general patterns that dominated the building of molecular biology in France. The study of the relationships between molecular biologists and biochemists or immunologists revealed the existence of alternatives to the development of operon research, or to the convergence with molecular biology. Both examples uncover specific paths leading to achievements that might be viewed as international trends: the expansion of RNA and translation studies, and the development of cellular immunology. They illustrate two possible patterns of linking local settings and disciplinary traditions: an oligopolistic situation where a few groups or one institution dominate an entire field, and the emergence of "collective" trends through collaboration networks or schools. (shrink)

Fred Sanger, the inventor of the first protein, RNA and DNA sequencing methods, has traditionally been seen as a technical scientist, engaged in laboratory bench work and not interested at all in intellectual debates in biology. In his autobiography and commentaries by fellow researchers, he is portrayed as having a trajectory exclusively dependent on technological progress. The scarce historical scholarship on Sanger partially challenges these accounts by highlighting the importance of professional contacts, institutional and disciplinary moves in his career, spanning (...) from 1940 to 1983. This paper will complement such literature by focusing, for the first time, on the transition of Sanger's sequencing strategies from degrading to copying the target molecule, which occurred in the late 1960s as he was shifting from protein and RNA to DNA sequencing, shortly after his move from the Department of Biochemistry to the Laboratory of Molecular Biology, both based in Cambridge (UK). Through a reinterpretation of Sanger's papers and retrospective accounts and a pioneering investigation of his laboratory notebooks, I will claim that sequencing shifted from the working procedures of organic chemistry to those of the emergent molecular biology. I will also argue that sequencing deserves a history in its own right as a practice and not as a technique subordinated to the development of molecular biology or genomics. My proposed history of sequencing leads to a reappraisal of current STS debates on bioinformatics, biotechnology and biomedicine. (shrink)

Fred Sanger, the inventor of the first protein, RNA and DNA sequencing methods, has traditionally been seen as a technical scientist, engaged in laboratory bench work and not interested at all in intellectual debates in biology. In his autobiography and commentaries by fellow researchers, he is portrayed as having a trajectory exclusively dependent on technological progress. The scarce historical scholarship on Sanger partially challenges these accounts by highlighting the importance of professional contacts, institutional and disciplinary moves in his career, spanning (...) from 1940 to 1983. This paper will complement such literature by focusing, for the first time, on the transition of Sanger’s sequencing strategies from degrading to copying the target molecule, which occurred in the late 1960s as he was shifting from protein and RNA to DNA sequencing, shortly after his move from the Department of Biochemistry to the Laboratory of Molecular Biology, both based in Cambridge (UK). Through a reinterpretation of Sanger’s papers and retrospective accounts and a pioneering investigation of his laboratory notebooks, I will claim that sequencing shifted from the working procedures of organic chemistry to those of the emergent molecular biology. I will also argue that sequencing deserves a history in its own right as a practice and not as a technique subordinated to the development of molecular biology or genomics. My proposed history of sequencing leads to a reappraisal of current STS debates on bioinformatics, biotechnology and biomedicine. (shrink)

This paper explores the different identities adopted by connective tissue research at the University of Manchester during the second half of the 20th century. By looking at the long-term redefinition of a research programme, it sheds new light on the interactions between different and conflicting levels in the study of biomedicine, such as the local and the global, or the medical and the biological. It also addresses the gap in the literature between the first biomedical complexes after World War II (...) and the emergence of biotechnology. Connective tissue research in Manchester emerged as a field focused on new treatments for rheumatic diseases. During the 1950s and 60s, it absorbed a number of laboratory techniques from biology, namely cell culture and electron microscopy. The transformations in scientific policy during the late 70s and the migration of Manchester researchers to the US led them to adopt recombinant DNA methods, which were borrowed from human genetics. This resulted in the emergence of cell matrix biology, a new field which had one of its reference centres in Manchester. The Manchester story shows the potential of detailed and chronologically wide local studies of patterns of work to understand the mechanisms by which new biomedical tools and institutions interact with long-standing problems and existing affiliations. (shrink)

Scientific hypotheses may either predict particular unknown facts or accommodate previously-known data. Although affirmed predictions are intuitively more rewarding than accommodations of established facts, opinions divide whether predictive hypotheses are also epistemically superior to accommodation hypotheses. This paper examines the contribution of predictive hypotheses to discoveries of several bio-molecular systems. Having all the necessary elements of the system known beforehand, an abstract predictive hypothesis of semiconservative mode of DNA replication was successfully affirmed. However, in defining the genetic code whose biochemical (...) basis was unclear, hypotheses were only partially effective and supplementary experimentation was required for its conclusive definition. Markedly, hypotheses were entirely inept in predicting workings of complex systems that included unknown elements. Thus, hypotheses did not predict the existence and function of mRNA, the multiple unidentified components of the protein biosynthesis machinery, or the manifold unknown constituents of the ubiquitin–proteasome system of protein breakdown. Consequently, because of their inability to envision unknown entities, predictive hypotheses did not contribute to the elucidation of cation theories remained the sole instrument to explain complex bio-molecular systems, the philosophical question of alleged advantage of predictive over accommodative hypotheses became inconsequential. (shrink)

Philosophers of science diverge on the question what drives the growth of scientific knowledge. Most of the twentieth century was dominated by the notion that theories propel that growth whereas experiments play secondary roles of operating within the theoretical framework or testing theoretical predictions. New experimentalism, a school of thought pioneered by Ian Hacking in the early 1980s, challenged this view by arguing that theory-free exploratory experimentation may in many cases effectively probe nature and potentially spawn higher evidence-based theories. Because (...) theories are often powerless to envisage workings of complex biological systems, theory-independent experimentation is common in the life sciences. Some such experiments are triggered by compelling observation, others are prompted by innovative techniques or instruments, whereas different investigations query big data to identify regularities and underlying organizing principles. A distinct fourth type of experiments is motivated by a major question. Here I describe two question-guided experimental discoveries in biochemistry: the cyclic adenosine monophosphate mediator of hormone action and the ubiquitin-mediated system of protein degradation. Lacking underlying theories, antecedent data bases, or new techniques, the sole guides of the two discoveries were respective substantial questions. Both research projects were similarly instigated by theory-free exploratory experimentation and continued in alternating phases of results-based interim working hypotheses, their examination by experiment, provisional hypotheses again, and so on. These two cases designate theory-free, question-guided, stepwise biochemical investigations as a distinct subtype of the new experimentalism mode of scientific enquiry. (shrink)

A longstanding philosophical premise perceives simplicity as a desirable attribute of scientific theories. One of several raised justifications for this notion is that simple theories are more likely to indicate the true makeup of natural systems. Qualitatively parsimonious hypotheses and theories keep to a minimum the number of different postulated entities within a system. Formulation of such ontologically simple working hypotheses proved to be useful in the experimental probing of narrowly defined bio systems. It is less certain, however, whether qualitatively (...) parsimonious theories are effective indicators of the true nature of complex biological systems. This paper assesses the success of ontologically simple theories in envisaging the makeup of three complex systems in bacteriology, immunology, and molecular biology. Evidence shows that parsimonious theories completely misconstrued the actual ontologically complex constitutions of the three examined systems. Since evolution and selective pressures typically produce ontologically intricate rather than simple bio systems, qualitatively parsimonious theories are mostly inapt indicators of the true nature of complex biological systems. (shrink)

This paper examines the vital role played by electron microscopy toward the modern definition of viruses, as formulated in the late 1950s. Before the 1930s viruses could neither be visualized by available technologies nor grown in artificial media. As such they were usually identified by their ability to cause diseases in their hosts and defined in such negative terms as “ultramicroscopic” or invisible infectious agents that could not be cultivated outside living cells. The invention of the electron microscope, with magnification (...) and resolution powers several orders of magnitude better than that of optical instruments, opened up possibilities for biological applications. The hitherto invisible viruses lent themselves especially well to investigation with this new instrument. We first offer a historical consideration of the development of the instrument and, more significantly, advances in techniques for preparing and observing specimens that turned the electron microscope into a routine biological tool. We then describe the ways in which the electron microscopic images, or micrographs, functioned as forms of new knowledge about viruses and resulted in a paradigm shift in the very definition of these entities. Micrographs were not mere illustrations since they did the work for the electron microscopists. Drawing extensively on primary publications, we adduce the role of the new instrument in understanding the so-called eclipse phase in virus multiplication and the unexpected spinoffs of data from electron microscopy in naming and classifying viruses. Thus, we show that electron microscopy functioned not only to provide evidence, but also arguments in facilitating a reordering of the world that it brought into the visual realm. (shrink)

: The main contribution of this paper for social studies of scientific practice is to use and further elaborate the concept of experimental system. It is expanded from mere epistemic concerns to also incorporate the built-in practicality and societal relevance of scientific research. For this, an analysis of object construction by a potato-biotechnology research group is presented. The group's object of activity is conceptualized as a dual one comprising both the epistemic and applied objectives. The application object points to the (...) virus-resistant cultivated potato under construction, the epistemic object to the knowledge on the virus-resistance mechanism. Two major phases of the group's work are perceived as distinct experimental systems. The transition between them is analysed in terms of a gradual evolution characterised by network collaboration, ad hoc improvization, resistance, opportunism and informal interaction. (shrink)