A new account of replication in the experimental life sciences

The life sciences are said to be in the midst of a replication crisis because (1) a majority of published results are irreproducible, and (2) scientists rarely replicate existing data. Here I argue that point 2 of this assessment is flawed because there is a hitherto unidentified form of replication in the experimental life sciences, which I call ‘microreplications’ (MRs). Using a case study from biochemistry, I illustrate how MRs depend on a key element of experimentation, namely, experimental controls. I end by reflecting on what MRs mean for the broader debate about the replication crisis

Trust in Science: CRISPR-Cas9 and the Ban on Human Germline Editing

This is the final version of the article. Available from Springer Verlag via the DOI in this record.In 2015 scientists called for a partial ban on genome editing in human germline cells. This call was a response to the rapid development of the CRISPR-Cas9 system, a molecular tool that allows researchers to modify genomic DNA in living organisms with high precision and ease of use. Importantly, the ban was meant to be a trust-building exercise that promises a 'prudent' way forward. The goal of this paper is to analyse whether the ban can deliver on this promise. To do so the focus will be put on the precedent on which the current ban is modelled, namely the Asilomar ban on recombinant DNA technology. The analysis of this case will show (a) that the Asilomar ban was successful because of a specific two-step containment strategy it employed and (b) that this two-step approach is also key to making the current ban work. It will be argued, however, that the Asilomar strategy cannot be transferred to human genome editing and that the current ban therefore fails to deliver on its promise. The paper will close with a reflection on the reasons for this failure and on what can be learned from it about the regulation of novel molecular tools.The research leading to this paper has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC Grant Agreement No. 324186

Editing the reactive genome: towards a postgenomic ethics of germline editing

The reported birth of genetically modified twins in late 2018 has given new fuel to debates about the ethics of germline genome editing (GGE). There is a broad consensus among stakeholders that clinical uses of GGE should be temporarily banned as the technology is not yet deemed safe for use in humans. However, the idea of a complete ban is dismissed by many based on the expectation that more research will eventually allow scientists to make the technology safe without having to put humans at risk first. In this article, I will analyse this assumption and argue that it is undermined by recent developments in the postgenomic life sciences. In particular, I will argue that in a postgenomic view of germline editing a complete ban on specific uses of the technology is warranted, because the research needed to assess the safety of these interventions would not be morally defensible

modENCODE and the elaboration of functional genomic methodology

A central tool in comparative genomics is sequence alignment. This makes it possible to identify stretches of DNA that exhibit different degrees of similarity across closely and distantly related organisms. In much of this work, phylogenetic conservation of sequence structure (i.e., homology) is a proxy for genomic function. After the Human Genome Project, there was growing interest in moving from structural or descriptive genomics to functional genomics. The goal of the ENCyclopedia Of DNA Elements (ENCODE) project was to identify and catalogue all the functional elements or active structures of the human genome. A parallel project attempted to catalogue shared functional elements of genomes across model organisms (modENCODE). The key methodological question for both projects was how to identify functional elements in the first place. As noted, an evolutionary approach uses comparative analysis of sequence similarity to identify sequence conservation across species, which is treated as a proxy for the functional relevance of those genomic elements. A biochemical approach focuses on signatures of activity that functional elements leave behind as proxies for the elements themselves. ENCODE primarily utilized the biochemical approach. modENCODE ended up doing something different and distinctive: it fused the biochemical and evolutionary approaches to genomic function and adopted an increased abstraction about what counts as a genomic property. This was a novel methodological maneuver. ENCODE focused on functional elements of the genome (i.e., structures), but modENCODE shifted to general regulatory principles (i.e., abstract functional rules). Evolutionary conservation is combined with biochemical activity to isolate shared relational functional properties—not elements or structures—of metazoan genomes. This methodological shift by modENCODE introduced a theoretical tension: the notion of conservation applies straightforwardly to sequence-based functional elements (i.e., structures), but less clearly to quantitative functional relationships. These rules are better described as prerequisites for how genomes operate rather than outcomes of evolutionary conservation. modENCODE identified distinctive physicochemical rules rather than mechanistic structure. These abstract, quantitative relationships are disconnected from modENCODE’s stated goal of discovering “how the information encoded in a genome can produce a complex multicellular organism.” Although modENCODE advanced our knowledge of how the genome works, it was relatively mute about the translation of genomic form into organismal complexity. The original research question was transformed in the process of inquiry: from detecting functional elements in the genome that contribute to organismal phenotypes, to identifying properties or rules of the genome that make it possible to function