Here we put on record contributions originally submitted for a workshop "Gene Concepts in Development and Evolution II", held in the fall of 1996. In the mean time, the main body of the workshop material has undergone changes and matured into a volume due to appear under a similar title at Cambridge University Press in the coming year. In this preprint we include commentaries on the original contributions made during the workshop or thereafter which will not be part of the published volume. Peter J. Beurton Raphael Falk Hans-Jörg Rheinberger GENE CONCEPTS IN DEVELOPMENT AND EVOLUTION GENE CONCEPTS: FRAGMENTS FROM THE PERSPECTIVE OF MOLECULAR BIOLOGY Hans-Jörg Rheinberger ........................................................................................... 3 Comments by Michel Morange ............................................................................ 20 THE DEVELOPMENTAL GENE CONCEPT: HISTORY AND LIMITS Michel Morange ................................................................................................... 25 Comments by Scott F. Gilbert .............................................................................. 43 DECODING THE GENETIC PROGRAM Evelyn Fox Keller ................................................................................................ 49 Comments by Thomas Fogle ................................................................................ 63 THE DISSOLUTION OF PROTEIN CODING GENES IN MOLECULAR BIOLOGY Thomas Fogle ....................................................................................................... 69 Comments by Fred Gifford .................................................................................. 88 A UNIFIED VIEW OF THE GENE, OR HOW TO OVERCOME REDUCTIONISM Peter John Beurton ............................................................................................... 97 Comments by James R. Griesemer .................................................................... 119 Comments by Thomas Fogle .............................................................................. 122 Addresses ........................................................................................................... 127 GENE CONCEPTS: FRAGMENTS FROM THE PERSPECTIVE OF MOLECULAR BIOLOGY Hans-Jörg Rheinberger "[It is] the vague, the unknown that moves the world" (Bernard 1954, p. 26). ABSTRACT The paper is divided in three parts. In the first part, I argue for an epistemology of the imprecise and try to characterize the historical and disciplinary trajectory of gene representations as the trajectory of an exemplar of a boundary object. In the second part, I follow the apparently sim- ple solution of the gene problem to which early molecular biology gave rise, and I retrace some of the steps and events through which the later development of molecular biology came to ex- plode this simple notion. The last part derives some conjectures from this story and seizes upon the notion of "integron" developed by François Jacob in order to establish a symmetrical per- spective on genomes and phenomes. 1. INTRODUCTION In what follows I intend to cast some light on the changing epistemic and experimental dispo- sitions through which molecular biology came to deal with genes. The paper is meant neither as a systematic assessment nor as a critique of the way molecular biology has appropriated this concept. Nor will I be able to retrace the history of the gene as an object of experimentation in molecular biology in all its complexity. My concern in this overview is to point out, in a loose and associative fashion, some questions that I think will have to be addressed if we wish to un- derstand where the second half of the twentieth century has taken us with respect to that unit that Herman J. Muller, on the occasion of the fiftieth anniversary of the rediscovery of Gregor Mendel's pea work, described with the following words: The real core of gene theory still appears to lie in the deep unknown. That is, we have as yet no actual knowledge of the mechanism underlying that unique property which makes a gene a gene - its ability to cause the synthesis of another structure like itself, in which even the mutations of the original gene are copied. ... We do not know of such things yet in chemistry (Muller 1951, pp. 95-96). These remarkable sentences were written in 1950. What has molecular biology taught us since then about those "unique properties which make a gene a gene"? No geneticist would repeat Muller's chemical ignoramus today. Yet we will see that instead of solving the riddle of the gene Hans-Jörg Rheinberger and rescuing it once for ever from the "deep unknown," molecular biology has managed to re- define its properties and its boundaries, and it has continued to change our conception of this strange entity repeatedly and almost beyond recognition. 2. EPISTEMOLOGY: FLUCTUATING OBJECTS AND IMPRECISE CONCEPTS If there are concepts endowed with organizing power in a research field, they are embedded in experimental operations. The practices in which the sciences are grounded engender epistemic objects, epistemic things as I call them, as targets of research. Despite their vagueness, these entities move the world of science. As a rule, disciplines become organized around one or a few of these "boundary objects" that underlie the conceptual translations between different domains (Star and Griesemer 1988). For a long time, in physics, such an object has been the atom; in chemistry, the molecule; in classical genetics, it became the gene. It is the historically changing set of epistemic practices that gives contours to these objects. According to received accounts, which I need not question here in depth, the boundary object of classical genetics has worked as a formal unit: That which, in an ever more sophisticated context of breeding experiments, accounts for the appearance or disappearance of certain characters that can be traced through subsequent generations. Accordingly, what has made classical genetics different from nine- teenth-century inquiries in heredity, is that its practice allowed to combine the notion of char- acter discreteness, rooted in the Darwinian and early De Vriesian traditions, with Weismann's distinction between germ plasm and body substance. The result, read back into Mendel's exper- iments, was a deliberate distinction between genetic units and unit characters; taken in their en- tirety, between genotype and phenotype, respectively. This is a reminder, and trivial to that extent. Let me give now an equivalent caricature of what molecular genetics has contributed to the field. At the beginning, molecular genetics, with its set of biochemical practices and genetic manipulations, was characterized by switching from higher plants and animals to bacteria and phages as model organisms. First, it transformed its boundary object, the gene, into a material, physico-chemical entity. Second, it has made of this object a unit endowed with informational qualities. The first transformation provided a solution to the problem that classical genetics had with the stability of its units. The answer was: Genes consist of metastable macromolecules of the sort of nucleic acids. The second transformation provided a solution to the problem that classical genetics had with its units' mode of reproduc- tion, and the connection between genotype and phenotype. The answer was: Nucleotide se- quences, and DNA in particular, can be replicated specifically and faithfully by virtue of the stereochemical properties of their building blocks. In addition, DNA stretches specify traits by 4 Gene Concepts: Fragments from the Perspective of Molecular Biology virtue of the ordered sequence of nucleotides they contain for being translated, with the help of a complex cytoplasmic machinery, into corresponding sequences of amino acids that yield structural proteins or enzymes catalyzing all sorts of metabolic reactions. What I would like to stress against this excessively schematic and simple-looking outline so suggestive in its clarity and distinctness after the event, is that the fruitfulness of boundary ob- jects in research does not depend on whether they can be given a precise and codified meaning from the outset. Stated otherwise, it is not necessary, indeed it can be rather counterproductive, to try to sharpen the conceptual boundaries of vaguely bounded research objects while in oper- ation. As long as the objects of research are in flux, the corresponding concepts must remain in flux, too (Elkana 1970). Boundary objects require boundary concepts. The fruitfulness of such concepts depends on their operational potential. "All definitions of the gene require operational criteria" (Portin 1993, p. 174). It is these criteria that make them work as definitions, if at all. The spectacular rise of molecular biology has come about without a comprehensive, exact, and rigid definition of what a gene is. As I will trace in the historical section of this essay, this claim can be substantiated for both aspects distinguishing the gene concept of molecular biology from that of classical genetics: The aspect of representing a material entity, and that of being a carrier of information (Sarkar 1996). The meaning of both of these notions has remained fuzzy and tied to the experimental spaces that the new biology was going to explore, from the identification of DNA as the hereditary material in bacteria in 1944 to the genome sequencing projects of the late 1980s. I am even inclined to postulate that attempts