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.

The Contributions - and Collapse - of Lamarckian Heredity in Pasteurian Molecular Biology: 1. Lysogeny, 1900-1960.

This article shows how Lamarckism was essential in the birth of the French school of molecular biology. We argue that the concept of inheritance of acquired characters positively shaped debates surrounding bacteriophagy and lysogeny in the Pasteurian tradition during the interwar period. During this period the typical Lamarckian account of heredity treated it as the continuation of protoplasmic physiology in daughter cells. Félix d'Hérelle applied this conception to argue that there was only one species of bacteriophage and Jules Bordet applied it to develop an account of bacteriophagy as a transmissible form of autolysis and to analyze the new phenomenon of lysogeny. In a long-standing controversy with Bordet, Eugène Wollman deployed a more morphological understanding of the inheritance of acquired characters, yielding a particulate, but still Lamarckian, account of lysogeny. We then turn to André Lwoff who, with several colleagues, completed Wollman's research program from 1949 to 1953. We examine how he gradually set aside the Lamarckian background, finally removing inheritance of acquired characters from the resulting account of bacteriophagy and lysogeny. In the conclusion, we emphasize the complex dual role of Lamarckism as it moved from an assumed explanatory framework to a challenge that the nascent molecular biology had to overcome.

Evolutionary analyses of non-genealogical bonds produced by introgressive descent.

All evolutionary biologists are familiar with evolutionary units that evolve by vertical descent in a tree-like fashion in single lineages. However, many other kinds of processes contribute to evolutionary diversity. In vertical descent, the genetic material of a particular evolutionary unit is propagated by replication inside its own lineage. In what we call introgressive descent, the genetic material of a particular evolutionary unit propagates into different host structures and is replicated within these host structures. Thus, introgressive descent generates a variety of evolutionary units and leaves recognizable patterns in resemblance networks. We characterize six kinds of evolutionary units, of which five involve mosaic lineages generated by introgressive descent. To facilitate detection of these units in resemblance networks, we introduce terminology based on two notions, P3s (subgraphs of three nodes: A, B, and C) and mosaic P3s, and suggest an apparatus for systematic detection of introgressive descent. Mosaic P3s correspond to a distinct type of evolutionary bond that is orthogonal to the bonds of kinship and genealogy usually examined by evolutionary biologists. We argue that recognition of these evolutionary bonds stimulates radical rethinking of key questions in evolutionary biology (e.g., the relations among evolutionary players in very early phases of evolutionary history, the origin and emergence of novelties, and the production of new lineages). This line of research will expand the study of biological complexity beyond the usual genealogical bonds, revealing additional sources of biodiversity. It provides an important step to a more realistic pluralist treatment of evolutionary complexity.

Hans-Jörg Rheinberger on biological time scales.

H.-J. Rheinberger (in Rheinberger 2002) analyzed the history of biological time concepts in very short compass. He begins with Newtonian time and Buffon's attempts to handle biological time. He then suggests an architectonic structure to account for three distinctive sorts of biological time. I summarize Rheinberger's account in this valuable essay, but criticize the architectonic as overly hierarchical (though Rheinberger also recognized relevant reticulation within the article) and for failing to appreciate sufficiently the interweaving of time scales in biological interactions.

Philosophy and evolution: minding the gap between evolutionary patterns and tree-like patterns.

Ever since Darwin, the familiar genealogical pattern known as the Tree of Life (TOL) has been prominent in evolutionary thinking and has dominated not only systematics, but also the analysis of the units of evolution. However, recent findings indicate that the evolution of DNA, especially in prokaryotes and such DNA vehicles as viruses and plasmids, does not follow a unique tree-like pattern. Because evolutionary patterns track a greater range of processes than those captured in genealogies, genealogical patterns are in fact only a subset of a broader set of evolutionary patterns. This fact suggests that evolutionists who focus exclusively on genealogical patterns are blocked from providing a significant range of genuine evolutionary explanations. Consequently, we highlight challenges to tree-based approaches, and point the way toward more appropriate methods to study evolution (although we do not present them in technical detail). We argue that there is significant benefit in adopting wider range of models, evolutionary representations, and evolutionary explanations, based on an analysis of the full range of evolutionary processes. We introduce an ecosystem orientation into evolutionary thinking that highlights the importance of "type 1 coalitions" (functionally related units with genetic exchanges, aka "friends with genetic benefits"), "type 2 coalitions" (functionally related units without genetic exchanges), "communal interactions," and "emergent evolutionary properties." On this basis, we seek to promote the study of (especially prokaryotic) evolution with dynamic evolutionary networks, which are less constrained than the TOL, and to provide new ways to analyze an expanded range of evolutionary units (genetic modules, recombined genes, plasmids, phages and prokaryotic genomes, pangenomes, microbial communities) and evolutionary processes. Finally, we discuss some of the conceptual and practical questions raised by such network-based representation.

From genetic to genomic regulation: iterativity in microRNA research.

The discovery and ongoing investigation of microRNAs (miRNAs) 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.

On microRNA and the need for exploratory experimentation in post-genomic molecular biology.

This paper is devoted to an examination of the discovery, characterization, and analysis of the functions of microRNAs, which also serves as a vehicle for demonstrating the importance of exploratory experimentation in current (post-genomic) molecular biology. The material on microRNAs is important in its own right: it provides important insight into the extreme complexity of regulatory networks involving components made of DNA, RNA, and protein. These networks play a central role in regulating development of multicellular organisms and illustrate the importance of epigenetic as well as genetic systems in evolution and development. The examination of these matters yields principled arguments for the historicity of the functions of key biological molecules and for the indispensability of exploratory experimentation in contemporary molecular biology as well as some insight into the complex interplay between exploratory experimentation and hypothesis-driven science. This latter result is not only important for philosophy of science, but also of practical importance for the evaluation of grant proposals, although the elaboration of this latter claim must be left for another occasion.

Molecular epigenesis, molecular pleiotropy, and molecular gene definitions.

Recent work on gene concepts has been influenced by recognition of the extent to which RNA transcripts from a given DNA sequence yield different products in different cellular environments. These transcripts are altered in many ways and yield many products based, somehow, on the sequence of nucleotides in the DNA. I focus on alternative splicing of RNA transcripts (which often yields distinct proteins from the same raw transcript) and on 'gene sharing', in which a single gene produces distinct proteins with the exact same amino acid sequence. These are instances of molecular pleiotropy, in which distinct molecules are derived from a single putative gene. In such cases the cellular and external environments play major roles in determining which protein is produced. Where there is molecular pleiotropy, alternative gene concepts are naturally deployed; molecular epigenesis (revision of sequence-based information by altering molecular conformations or by action of non-informational molecules) plays a major role in orderly development. These results show that gene concepts in molecular biology do, and should, have both structural and functional components. They also show the need for a plurality of gene concepts and reveal fundamental difficulties in stabilizing gene concepts solely by reference to nucleotide sequence.