Experimental Systems in the Co-Construction of Scientific Knowledge.

The publication of Toward a History of Epistemic Things 25 years ago was a landmark in science studies. Not only was the book a brilliant overview of new research trends, but it was also a personal and highly original contribution because of its emphasis on the major role of experimental systems in the construction of scientific knowledge. The paths that it opened have not yet been fully explored. More seriously, the ambition of the author to reinforce the value of scientific knowledge by the role of experimental systems in its construction has not been pursued.

Pseudoalleles and Gene Complexes: The Search for the Elusive Link Between Genome Structure and Gene Function.

After their discovery in the first decades of the 20th century, pseudo-alleles generated much interest among geneticists, because they apparently violated the conception of the genome as a collection of independent genes, a view elaborated by Thomas Morgan's group. This article focuses on two issues: the way the phenomenon of pseudoallelism suggests that the genome is more than a simple addition of independent genes, and the connection established between the formation of pseudoalleles during evolution and their functional roles. The article discusses the first explanations for the origin of pseudoalleles elaborated in the mid-1930s, the metabolic/developmental sequential model proposed by Ed Lewis in the 1950s, the disappointments encountered with the T-complex in the 1970s, and the fading of the previous models after the molecular characterization of the pseudoallelic gene complexes in the 1980s. Genomes are more than collections of genes, but their structures are the result of a complex evolutionary history that leaves no place for simplistic models.

Genome as a multipurpose structure built by evolution.

The 2012 publication of the results of the ENCODE program generated an acrimonious debate about the role of junk DNA. This debate is a symptom of the difficulties of dovetailing functional and evolutionary descriptions of genomes. This essay argues that extant genomes are the result of a progressive evolutionary construction. To the basic function that gives rise to RNA and proteins have been successively added additional functions, such as regulation by microRNA and epigenetic marks. This process of complexification was the result of evolutionary history, and different for the different genomes. Better knowledge of the evolutionary history of genomes would help to understand these structures and their functions.

[Hypotheses for the genesis of cancer: a historical perspective]. / Les modèles explicatifs du cancer - aspects historiques.

The explanation of cancer has always been tightly related to the state of knowledge in biology, and its transformations. The present situation is not different. New techniques, such as deep sequencing, are rapidly moving our vision of cancer in an impredictable way. Systems biology, epigenetics, and the study of stem cells are generating new hypotheses on cancer and its evolution. New roles for aleatory events in the genesis of cancer have been proposed. In the traditional opposition between holism and reductionism, organisms and molecules, an intermediary level, the cancer cell, seems to be the most appropriate to study oncogenesis.

Evolutionary developmental biology its roots and characteristics.

The rise of evolutionary developmental biology was not the progressive isolation and characterization of developmental genes and gene networks. Many obstacles had to be overcome: the idea that all genes were more or less involved in development; the evidence that developmental processes in insects had nothing in common with those of vertebrates. Different lines of research converged toward the creation of evolutionary developmental biology, giving this field of research its present heterogeneity. This does not prevent all those working in the field from sharing the conviction that a precise characterization of evolutionary variations is required to fully understand the evolutionary process. Some evolutionary developmental biologists directly challenge the Modern Synthesis. I propose some ways to reconcile these apparently opposed visions of evolution. The turbulence seen in evolutionary developmental biology reflects the present entry of history into biology.

Synthetic biology: a challenge to mechanical explanations in biology?

In their plans to modify organisms, synthetic biologists have contrasted engineering and tinkering. By drawing this contrast between their endeavors and what has happened during the evolution of organisms by natural selection, they underline the novelty of their projects and justify their ambitions. Synthetic biologists are at odds with a long tradition that has considered organisms as "perfect machines." This tradition had already been questioned by Stephen Jay Gould in the 1970s and received a major blow with the comparison made by François Jacob between organisms and the results of "bricolage" (tinkering). These contrasts between engineering and tinkering, synthetic biology and evolution, have no raison d'être. Machines built by humans are increasingly inspired by observations made on organisms. This is not a simple reversal of the previous trend-the mechanical conception of organisms-in which the characteristics of the latter were explained by comparison with human-built machines. Relations between organisms and machines have always been complex and ambiguous.

The resurrection of life.

The question of life was progressively put aside in the second half of the 20th century with the rise of molecular biology, but has recently re-emerged. Many scientists and philosophers consider that there is no place for this question within biology; that the distinction between living and non-living is arbitrary; and that progress in synthetic biology will finally put this question out of people's minds. I will argue that there is something wrong with the arguments supporting these statements. There are no reasons to exclude the question "What is life?" from biology. But the nature of the question has dramatically changed recently. Instead of being a search for the principles of life, the answer is now sought in the description of the historical process that has coupled the now well-established characteristics of organisms.

A Time to Model and a Time to Experiment.

The nature and role of models have been amply discussed by philosophers of science. They have emphasized the diversity of models and their functions. Biological sciences in general, and molecular and cellular biology in particular, are no exceptions. The nature and role of models in molecular and cellular biology are also a legacy of the different disciplines that contributed to its formation. Models can be a step toward abstraction, or the opposite, a step toward a material representation of an-to date-abstract phenomenon. Models can also help to collect information and knowledge. I will consider different models that played a highly important role in molecular and cellular biology, up to the Gene Regulatory Network model. There is a right time to model, and a right way to do it. I will try to understand why a model is well received (or not), and what kind of relationship it may or must have with experiments and experimental data.

Homage to Eric Davidson.

The Britten-Davidson model of genetic regulation was well received by American molecular biologists and embryologists, but not by the members of the French School of molecular biology. In particular, François Jacob considered it too abstract and too removed from experiments. I re-examine the contrast between the Britten-Davidson model and the operon model by Jacob and Monod, the different scientific contexts in which they were produced and the different roles they played. I also describe my recent encounters with Eric Davidson, and how I discovered the extraordinary continuity of his work on the development of the sea urchin, as well as his rich personality.

Human germline editing: a historical perspective.

The development of the genome editing system called CRISPR-Cas9 has opened a huge debate on the possibility of modifying the human germline. But the types of changes that could and/or ought to be made have not been discussed. To cast some light on this debate, I will describe the story of the CRISPR-Cas9 system. Then, I will briefly review the projects for modification of the human species that were discussed by biologists throughout the twentieth century. Lastly, I will show that for plenty of reasons, both scientific and societal, germline modification is no longer a priority for our societies.

Introduction: Eric Davidson and the molecular biology of evolution and development.

Between November 30th and December 2nd, 2015, the Jacques Loeb Centre for the History and Philosophy of the Life Sciences at Ben-Gurion University of the Negev in Beer Sheva (Israel) held its Eighth International Workshop under the title "From Genome to Gene: Causality, Synthesis and Evolution". Eric Davidson, the founder of the concept of developmental Gene Regulatory Networks, had regularly attended the previous meetings, and his participation in this one was expected, but he suddenly passed away 3 months before. In this paper, we provide an introduction and overview on five papers that were presented at the workshop and examine the importance of genomes and gene regulatory networks in extant biology, developmental biology, evolutionary biology and medicine, as well as a collection of remembrances of Eric Davidson, of his personality as well as of his scientific contributions. Historical perspectives are provided, and the ethical issues raised by the new tools developed to modify the genome are also discussed.

Heat shock protein 25 plays multiple roles during mouse skin development.

Heat shock protein (Hsp) 25 is a member of the small Hsp family. High levels of Hsp25 can be detected in skin. During adult epidermis differentiation, the concentration of Hsp25 increases as the distance of keratinocytes from the basal layer increases, in parallel with the extent of keratinization. We previously showed that Hsp25, mouse keratin (MK) 5, and MK14 participated in the formation of characteristic ring-shaped aggregates during the differentiation of the PAM212 keratinocyte cell line. We suggested that Hsp25 was involved in the disorganization of the MK5-MK14 keratin network before the establishment of the MK1-MK10 keratin network at the beginning of epidermis stratification. In this study, we have investigated the distribution of Hsp25 and keratins throughout skin development. We demonstrate that the distribution of Hsp25 and MK5 in the epidermis at the beginning of stratification and before keratinization is similar to that observed in PAM212 keratinocytes. These results indicate that there is a strong correlation between the mechanism we described ex vivo and the events taking place in vivo. Moreover, we show that Hsp25 is produced in different cell types in the epidermis and in the hair follicle at different stages of their development. Thus, our results suggest that Hsp25 is involved in more than one process during skin development.

[How to localize epigenetics in the landscape of biological research?]. / Quelle place pour l'épigénétique?

Today, epigenetics is a very fashionable field of research. Modification of DNA by methylation, and of chromatin by histone modification or substitution represents a major fraction of the studies; but this special issue shows that epigenetic studies are very diverse, and not limited to the study of chromatin. What is common behind these different uses of the word epigenetics? A brief historical survey shows that epigenetics was invented twice, with different meanings: in the 1940s, by Conrad Waddington, as the study of the relations between the genotype and the phenotype; in the 1960s, as the global mechanisms of gene regulation involved in differentiation and development; what is common is that an approach distinct from genetics was in both cases considered as necessary because genetic models were incapable to address these problems. A good way to appreciate the relations between genetics and epigenetics is to realize that the main aim of organisms is to reproduce, and to consider the way organisms perform this task. Genetics is the precise means organisms have invented to reproduce the structure of their macromolecular components; the genome is also used to control the level and place of this reproduction. All the other means organisms have used to reproduce were more or less the result of tinkering, and constitute the field of epigenetics, with its diversity and richness.