In lieu of an abstract, here is a brief excerpt of the content:Kennedy Institute of Ethics Journal 14.1 (2004) 47-54 [Access article in PDF] Ethical Guidelines for Human Embryonic Stem Cell Research*(A Recommended Manuscript) Adopted on 16 October 2001Revised on 20 August 2002 Ethics Committee of the Chinese National Human Genome Center at Shanghai, Shanghai 201203 Human embryonic stem cell (ES) research is a great project in the frontier of biomedical science for the twenty-first century. Be- cause the research involves (...) the use of human embryos, it triggers serious debate on ethical issues. Opponents consider the embryo to be an early form of human life that should be respected and not destroyed. However, the majority of scientists support embryonic stem cell research, believing that it offers good prospects for the treatment of diseases that have remained incurable until now and so will benefit humankind. The Ethics Committee of the Department of Ethical, Legal, and Social Implications of the Chinese National Human Genome Center at Shanghai seriously discussed the ethical debate initiated by embryonic stem cell research. We concluded that we should support the scientists of our country in actively carrying out human embryonic stem cell research for the noble cause of "medicine being a beneficent art." For the healthy and orderly development of human embryonic stem cell research in our country, we put forward the following recommended Ethical Guidelines for Human Embryonic Stem Cell Research as a reference for leaders, administrative departments, and related scientists. Preface Article 1. Human embryonic stem cells are the primitive cells that play the main role in the growth and development of a human body. These [End Page 47] primitive cells have the potential for infinite proliferation, self-renewal, and multi-directional differentiation. If scientists can discover the mechanism of differentiation of human embryonic stem cells, it will be possible to induce differentiation of human embryonic stem cells to form various types of human cells for clinical cell therapy. If human embryonic stem cell research can be integrated with modern biomedical engineering techniques, it also will be possible to make repair and replacement of human tissues and organs a reality. Article 2. There are two ways to classify human embryonic stem cells. One way is to classify them according to their potential for differentiation. There could be three kinds of stem cells: totipotent stem cells, pluripotent stem cells, and unipotent stem cells.A totipotent stem cell has the potential to develop into a whole individual. It can differentiate into the more than 200 cell types in the whole body, construct any tissue or organ of the body, and finally develop into a whole individual. The fertilized egg and the cleavage cells at the very early stage of embryonic development are totipotent stem cells.A pluripotent stem cell has the potential to differentiate into many cell types derived from the three embryonic layers. However, it has lost the capacity to develop into a complete organism.A unipotent stem cell is derived from the further differentiation of the pluripotent stem cell. It can differentiate only into one cell type such as a hematopoietic stem cell, neural stem cell, and others.The other way is to classify human stem cells according to their source. There could be two kinds of human stem cells: embryonic stem cells and tissue stem cells (also called adult stem cells). The former involves experimentation with embryos, which has serious ethical implications. Ethical issues associated with the latter are mainly expressed in the various opinions regarding the allocation of health resources. Article 3. Human embryonic stem cells are the group of cells called the blastocyst inner cell mass during the early stage of embryonic development. They are the main source of totipotent stem cells, and hence the focal and hot point in stem cell research. Studies on the clinical application of embryonic stem cells probably will involve use of the somatic cell nucleus transfer (SCNT) technique, which destroys the early human embryo. At present, the ethical and moral debate is very serious in human embryonic stem cell research regarding whether the research will develop... (shrink)

Few topics have intrigued biologists as much as the evolution of sex. Understanding why sex persists despite its costs requires not just rigorous theoretical study, but also empirical data on related fundamental issues, including the nature of genetic variance for fitness, patterns of genetic interactions, and the dynamics of adaptation. The increasing feasibility of examining genomes in an experimental context is now shedding new light on these problems. Using this approach, McDonald et al. recently demonstrated that sex uncouples beneficial (...) and deleterious mutations, allowing selection to proceed more effectively with sex than without. Here we discuss the insights provided by this study, along with other recent empirical work, in the context of the major theoretical models for the evolution of sex. (shrink)

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. (shrink)

Biotechnology might contribute to solving food safety and security challenges. However, gene technology has been under public scrutiny, linked to the framing of the media and public discourse. The study aims to investigate people’s perceptions and acceptance of food biotechnology with focus on transgenic genetic modification versus genome editing. An online experiment was conducted with participants from the United Kingdom and Switzerland. The participants were presented with the topic of food biotechnology and more specifically with experimentally varied vignettes on transgenic (...) and genetic modification and genome editing. The results suggest that participants from both countries express higher levels of acceptance for genome editing compared to transgenic genetic modification. The general and personal acceptance of these technologies depend largely on whether the participants believe the application is beneficial, how they perceive scientific uncertainty, and the country they reside in. Our findings suggest that future communication about gene technology should focus more on discussing trade-offs between using an agricultural technologies and tangible and relevant benefits, instead of a unidimensional focus on risk and safety. (shrink)

In my field, animal developmental biology, and in what could be regarded as its “deep time derivative,” the evolutionary biology of the animal body plan, there exist two kinds of experimentally supported causal explanation. These can be described as “rooted” and “unrooted.” Rooted causal explanation provides logical links to and from the genomic regulatory code, extending right into the genomic sequences that control regulatory gene expression. The genomic regulatory code ultimately determines the developmental process in a direct way, since subsequent (...) developmental events all depend directly and specifically on what regulatory genes are being expressed and where in the developing organism they are being expressed.. (shrink)

New concepts may prove necessary to profit from the avalanche of sequence data on the genome, transcriptome, proteome and interactome and to relate this information to cell physiology. Here, we focus on the concept of large activity-based structures, or hyperstructures, in which a variety of types of molecules are brought together to perform a function. We review the evidence for the existence of hyperstructures responsible for the initiation of DNA replication, the sequestration of newly replicated origins of replication, cell division (...) and for metabolism. The processes responsible for hyperstructure formation include changes in enzyme affinities due to metabolite-induction, lipid-protein affinities, elevated local concentrations of proteins and their binding sites on DNA and RNA, and transertion. Experimental techniques exist that can be used to study hyperstructures and we review some of the ones less familiar to biologists. Finally, we speculate on how a variety of in silico approaches involving cellular automata and multi-agent systems could be combined to develop new concepts in the form of an Integrated cell (I-cell) which would undergo selection for growth and survival in a world of artificial microbiology. (shrink)

Evidence for recombination suppression has been identified in linkage studies of several unstable DNA diseases. Also sex‐specific changes in recombination frequency have been detected at the loci of Huntington's disease and myotonic dystrophy. It can be hypothesized that meiotic recombination is regulated by genome‐wide genomic imprinting and that changes in meiotic recombination imply the presence of the genomic imprinting defect. If aberrant recombination at the locus of trinucleotide repeat expansion is verified, new theoretical and experimental opportunities will arise in (...) studies on the role of genomic imprinting in the unstable DNA diseases. (shrink)

Drosophila melanogaster is often considered to lack genomic 5‐methylcytosine (m5C), an opinion reinforced by two whole genome bisulfite‐sequencing studies that failed to find m5C. New evidence, however, indicates that genomic methylation is indeed present in the fly, albeit in small quantities and in unusual patterns. At embryonic stage 5, m5C occurs in short strand‐specific regions that cover ∼1% of the genome, at tissue levels suggesting a distribution restricted to a subset of nuclei. Its function is not obvious, but methylation in (...) subsets of nuclei would obscure functional associations since transcript levels and epigenetic modifications are assayed in whole embryos. Surprisingly, Mt2, the fly's only candidate DNA methyltransferase, is not necessary for the observed methylation. Full evaluation of the functions of genome methylation in Drosophila must await discovery and experimental inactivation of the DNA methyltransferase, as well as a better understanding of the pattern and developmental regulation of genomic m5C. (shrink)

The Planteome project provides a suite of reference and species-specific ontologies for plants and annotations to genes and phenotypes. Ontologies serve as common standards for semantic integration of a large and growing corpus of plant genomics, phenomics and genetics data. The reference ontologies include the Plant Ontology, Plant Trait Ontology, and the Plant Experimental Conditions Ontology developed by the Planteome project, along with the Gene Ontology, Chemical Entities of Biological Interest, Phenotype and Attribute Ontology, and others. The project (...) also provides access to species-specific Crop Ontologies developed by various plant breeding and research communities from around the world. We provide integrated data on plant traits, phenotypes, and gene function and expression from 95 plant taxa, annotated with reference ontology terms. (shrink)

In recent years, CRISPR-Cas9 has become one of the simplest and most cost-effective genetic engineering techniques among scientists and researchers aiming to alter genes in organisms. As Zika came to the fore as a global health crisis, many suggested the use of CRISPR-Cas9 gene drives in mosquitoes as a possible means to prevent the transmission of the virus without the need to subject humans to risky experimental treatments. This paper suggests that using gene drives or other forms of genome (...) editing in nonhumans (like mosquitos) for the purposes of disease prevention raises important issues about informed consent. Additionally, it examines the consequences this line of inquiry could have for the use of gene drives as a tool in public health and suggests that the guidance offered by informed consent protocols could help the scientific community deploy gene drives in a way that ensures that ongoing research is consistent with our ethical priorities. (shrink)

The presence and role of microbes in human cancers has come full circle in the last century. Tumors are no longer considered aseptic, but implications for cancer biology and oncology remain underappreciated. Opportunities to identify and build translational diagnostics, prognostics, and therapeutics that exploit cancer's second genome—the metagenome—are manifold, but require careful consideration of microbial experimental idiosyncrasies that are distinct from host‐centric methods. Furthermore, the discoveries of intracellular and intra‐metastatic cancer bacteria necessitate fundamental changes in describing clonal evolution and (...) selection, reflecting bidirectional interactions with non‐human residents. Reconsidering cancer clonality as a multispecies process similarly holds key implications for understanding metastasis and prognosing therapeutic resistance while providing rational guidance for the next generation of bacterial cancer therapies. Guided by these new findings and challenges, this Review describes opportunities to exploit cancer's metagenome in oncology and proposes an evolutionary framework as a first step towards modeling multispecies cancer clonality. Also see the video abstract here: https://youtu.be/-WDtIRJYZSs. (shrink)

NCG 4.0 is the latest update of the Network of Cancer Genes, a web-based repository of systems-level properties of cancer genes. In its current version, the database collects information on 537 known (i.e. experimentally supported) and 1463 candidate (i.e. inferred using statistical methods) cancer genes. Candidate cancer genes derive from the manual revision of 67 original publications describing the mutational screening of 3460 human exomes and genomes in 23 different cancer types. For all 2000 cancer genes, duplicability, evolutionary origin, expression, (...) functional annotation, interaction network with other human proteins and with microRNAs are reported. In addition to providing a substantial update of cancer-related information, NCG 4.0 also introduces two new features. The first is the annotation of possible false-positive cancer drivers, defined as candidate cancer genes inferred from large-scale screenings whose association with cancer is likely to be spurious. The second is the description of the systems-level properties of 64 human microRNAs that are causally involved in cancer progression (oncomiRs). Owing to the manual revision of all information, NCG 4.0 constitutes a complete and reliable resource on human coding and non-coding genes whose deregulation drives cancer onset and/or progression. NCG 4.0 can also be downloaded as a free application for Android smart phones. (shrink)

Recombinant DNA technology is an essential area of life engineering. The main aim of research in this field is to experimentally explore the possibilities of repairing damaged human DNA, healing or enhancing future human bodies. Based on ethnographic research in a Czech biochemical laboratory, the article explores biotechnological corporealities and their specific ontology through dealings with bio-objects, the bodywork of scientists. Using the complementary concepts of utopia and heterotopia, the text addresses the situation of bodies and bio-objects in a laboratory. (...) Embodied utopias are analyzed as material semiotic phenomena that are embodied by scientists in their visions and emotions and that are related to potential bodies and to future, not-yet-actualized embodiments. As a counterpart to this, the text explores embodied heterotopias, which are always the other spaces, like biotechnological bio-objects that are simulated in computers or stored in special solutions. (shrink)

Plastids and mitochondria arose through endosymbiotic acquisition of formerly free-living bacteria. During more than a billion years of subsequent concerted evolution, the three genomes of plant cells have undergone dramatic structural changes to optimize the expression of the compartmentalized genetic material and to fine-tune the communication between the nucleus and the organelles. The chimeric composition of many multiprotein complexes in plastids and mitochondria (one part of the subunits being nuclear encoded and another one being encoded in the organellar genome) provides (...) a paradigm for co-evolution at the cellular level. In this paper, we discuss the co-evolution of nuclear and organellar genomes in the context of environmental adaptation in species and populations. We highlight emerging genetic model systems and new experimental approaches that are particularly suitable to elucidate the molecular basis of co-adaptation processes and describe how nuclear-cytoplasmic co-evolution can cause genetic incompatibilities that contribute to the establishment of hybridization barriers, ultimately leading to the formation of new species. (shrink)

The purpose of this article is to update and defend syntax-based gene concepts. I show how syntax-based concepts can and have been extended to accommodate complex cases of processing and gene expression regulation. In response to difficult cases and causal parity objections, I argue that a syntax-based approach fleshes out a deflationary concept defining genes as genomic sequences and organizational features of the genome contributing to a phenotype. These organizational features are an important part of accepted molecular explanations, provide the (...) theoretical basis for a large number of experimental techniques and practical applications, and play a crucial role in in annotating the genome, deriving predictions and constructing bioinformatics models. (shrink)

This article traces the rapid progression of policy pertaining to human genome germline modifications using genome editing. It provides an overview of how one fertility physician implemented and advertised experimental techniques as part of his fertility clinic services, examines US law and policy, and assesses the impact of rhetoric influencing global policy and interpretation of the law. This article provides an in-depth examination of the medical rationale driving the acceptance of genome editing human embryos in two contexts: to cure (...) disease and treat infertility. It describes complexities in genomics and outlines risks currently associated with genome editing, asserting the available evidence fails to demonstrate genome editing constitutes a curative therapy. (shrink)

In 1991, Linda Buck and Richard Axel identified the multigene family expressing odor receptors. Their discovery transformed research on olfaction overnight, and Buck and Axel were awarded the 2004 Nobel Prize in Physiology or Medicine. Behind this success lies another, less visible study about the methodological ingenuity of Buck. This hidden tale holds the key to answering a fundamental question in discovery analysis: What makes specific discovery tools fit their tasks? Why do some strategies turn out to be more fruitful (...) than others? The fit of a method with an experimental system often establishes the success of a discovery. However, the underlying reasoning of discovery is hard to codify. These difficulties point toward an element of discovery analysis routinely sidelined as a mere biographical element in the philosophical analysis of science: the individual discoverer’s role. I argue that the individual researcher is not a replaceable epistemic element in discovery analysis. This article draws on contemporary oral history, including interviews with Buck and other actors key to developments in late 1980s olfaction. (shrink)

The importance of viruses as model organisms is well-established in molecular biology and Max Delbrück's phage group set standards in the DNA phage field. In this paper, I argue that RNA phages, discovered in the 1960s, were also instrumental in the making of molecular biology. As part of experimental systems, RNA phages stood for messenger RNA (mRNA), genes and genome. RNA was thought to mediate information transfers between DNA and proteins. Furthermore, RNA was more manageable at the bench than (...) DNA due to the availability of specific RNases, enzymes used as chemical tools to analyse RNA. Finally, RNA phages provided scientists with a pure source of mRNA to investigate the genetic code, genes and even a genome sequence. This paper focuses on Walter Fiers’ laboratory at Ghent University (Belgium) and their work on the RNA phage MS2. When setting up his Laboratory of Molecular Biology, Fiers planned a comprehensive study of the virus with a strong emphasis on the issue of structure. In his lab, RNA sequencing, now a little-known technique, evolved gradually from a means to solve the genetic code, to a tool for completing the first genome sequence. Thus, I follow the research pathway of Fiers and his ‘RNA phage lab’ with their evolving experimental system from 1960 to the late 1970s. This study illuminates two decisive shifts in post-war biology: the emergence of molecular biology as a discipline in the 1960s in Europe and of genomics in the 1990s. (shrink)

Knowledge of the structure of ancestral genomes provides the basis of a new framework to better represent and interpret results from genomic and evolutionary studies. Because these ancestors lived tens of hundreds of million years ago, this knowledge will inevitably take the form of abstract representations, reconstructed on the basis both of experimental evidence collected on extant genomes and of our understanding of evolutionary processes. This is the field of Paleogenomics, a young discipline that is providing an increasingly precise (...) picture of our ancestral vertebrate genomes based on cytogenetic data, genome sequences and new algorithmic developments. Many recent studies have focused on the ancestral placental mammal and teleost fish genomes, although the outlines of even more distant pre‐vertebrate ancestors are being reported. BioEssays 30:122–134, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

In 2012, we published a computational automaton, based on the most comprehensive gene regulatory network (GRN) model yet available (Peter, Faure, and Davidson 2012). This model had been synthesized over the previous years from extensive experimental studies on specification mechanisms in the endomesodermal territories of the sea urchin embryo. The GRN model explicitly indicated the dynamically changing interactions occurring at the cis-regulatory control sequences of almost 50 genes, mostly encoding transcription factors (the proteins that specifically recognize cis-regulatory DNA sequence (...) and cause expression or inactivity of the genes these sequences control). The GRN model encompasses all regulatory genes .. (shrink)

Rattus norvegicus is an important experimental organism and interesting to evolutionary biologists. The recently published draft rat genome sequence1 provides us with insights into both the rat's evolution and its physiology. We learn more about genome evolution and, in particular, the adaptive significance of gene family expansions and the evolution of rodent genomes, which appears to have decelerated since the divergence of mouse and rat. An important observation is that some regions of genomes, many in noncoding regions, show very (...) high sequence conservation, while others show unexpectedly fast evolution. Both of these may be pointers to functional significance. BioEssays 26:1039–1042, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Various algorithms have been proposed for learning (partial) genetic regulatory networks through systematic measurements of differential expression in wild type versus strains in which expression of specific genes has been suppressed or enhanced, as well as for determining the most informative next experiment in a sequence. While the behavior of these algorithms has been investigated for toy examples, the full computational complexity of the problem has not received sufficient attention. We show that finding the true regulatory network requires (in the (...) worst-case) exponentially many experiments (in the number of genes). Perhaps more importantly, we provide an algorithm for determining the set of regulatory networks consistent with the observed data. We then show that this algorithm is infeasible for realistic data (specifically, nine genes and ten experiments). This infeasibility is not due to an algorithmic flaw, but rather to the fact that there are far too many networks consistent with the data (10 18 in the provided example). We conclude that gene perturbation experiments are useful in confirming regulatory network models discovered by other techniques, but not a feasible search strategy. (shrink)

In this paper, I examine an experimental technique, gene targeting, used for establishing genotype/phenotype relationships. Through analyzing a case study, I identify many pitfalls that may lead to false conclusions about these relationships. I argue that some of these pitfalls may seriously affect gene targeting's usefulness for associating phenotypes with genes cataloged by the Human Genome Project. This case also shows the use of gene targeted mice as model systems for studying genotype/phenotype relationships in humans. Moreover, I argue that (...) it reveals the weakness of one attempt to draw conclusions about the biological determination of sexual and aggressive behaviors in humans. (shrink)

The importance of viruses as model organisms is well-established in molecular biology and Max Delbrück’s phage group set standards in the DNA phage field. In this paper, I argue that RNA phages, discovered in the 1960s, were also instrumental in the making of molecular biology. As part of experimental systems, RNA phages stood for messenger RNA, genes and genome. RNA was thought to mediate information transfers between DNA and proteins. Furthermore, RNA was more manageable at the bench than DNA (...) due to the availability of specific RNases, enzymes used as chemical tools to analyse RNA. Finally, RNA phages provided scientists with a pure source of mRNA to investigate the genetic code, genes and even a genome sequence. This paper focuses on Walter Fiers’ laboratory at Ghent University and their work on the RNA phage MS2. When setting up his Laboratory of Molecular Biology, Fiers planned a comprehensive study of the virus with a strong emphasis on the issue of structure. In his lab, RNA sequencing, now a little-known technique, evolved gradually from a means to solve the genetic code, to a tool for completing the first genome sequence. Thus, I follow the research pathway of Fiers and his ‘RNA phage lab’ with their evolving experimental system from 1960 to the late 1970s. This study illuminates two decisive shifts in post-war biology: the emergence of molecular biology as a discipline in the 1960s in Europe and of genomics in the 1990s. (shrink)

Ecological developmental biology (eco‐devo) explores the mechanistic relationships between the processes of individual development and environmental factors. Recent studies imply that some of these relationships have deep evolutionary origins, and may even pre‐date the divergences of the simplest extant animals, including cnidarians and sponges. Development of these early diverging metazoans is often sensitive to environmental factors, and these interactions occur in the context of conserved signaling pathways and mechanisms of tissue homeostasis whose detailed molecular logic remain elusive. Efficient methods for (...) transgenesis in cnidarians together with the ease of experimental manipulation in cnidarians and sponges make them ideal models for understanding causal relationships between environmental factors and developmental mechanisms. Here, we identify major questions at the interface between animal evolution and development and outline a road map for research aimed at identifying the mechanisms that link environmental factors to developmental mechanisms in early diverging metazoans.Also watch the Video Abstract. (shrink)

Diatoms are a species‐rich group of photosynthetic eukaryotes, with enormous ecological significance and great potential for biotechnology. During the last decade, diatoms have begun to be studied intensively using modern molecular techniques and the genomes of four diatoms have been wholly or partially sequenced. Although new insights into the biology and evolution of diatoms are accumulating rapidly due to the availability of reverse genetic tools, the full potential of these molecular biological approaches can only be fully realized if experimental (...) control of sexual crosses becomes firmly established and widely accessible to experimental biologists. Here we discuss the issue of choosing new models for diatom research, by taking into account the broader context of diatom mating systems and the place of sex in relation to the intricate cycle of cell size reduction and restitution that is characteristic of most diatoms. We illustrate the results of our efforts to select and develop experimental systems in diatoms, using species with typical life cycle attributes, which could be used as future model organisms to complement existing ones. BioEssays 30:692–702, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

In the genomics era, bioinformatic analysis, especially in non‐model species, facilitates the identification and naming of numerous new proteins, the function of which is then inferred through homology searches. Here, we question certain aspects of these approaches. What are the criteria that permit such a determination? What are their limits? Naming is classifying. We review the different criteria that are used to name a protein and discuss their constraints. We observe that the name given to a protein often introduces (...) a bias for further functional analyses, a bias that is not often taken into account when analysing results. Last but not least, the heterogeneity of criteria used for naming proteins leads to self‐inconsistent or contradictory protein classification that is potentially misleading. Finally, we recommend a wider use of phylogenetic criteria in protein naming. BioEssays 30:349–357, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Neurobiology studies mechanisms of cell signalling. A key question is how cells recognise specific signals. In this context, olfaction has become an important experimental system over the past 25 years. The olfactory system responds to an array of structurally diverse stimuli. The discovery of the olfactory receptors (ORs), recognising these stimuli, established the olfactory pathway as part of a greater group of signalling mechanisms mediated by G-protein-coupled receptors (GPCRs). GPCRs are the largest protein family in the mammalian genome and (...) involved in numerous fundamental physiological processes. The OR family exhibits two characteristics that make them an excellent model system to understand GPCRs: its size and the structural diversity of its members. Research on the OR binding site investigates what amino acid sequences determine the receptor-binding capacity. This promises a better understanding of how the basic genetic makeup of GPCRs relates to their diversification in ligand-binding capacities. (shrink)

Paul Griffiths and John Matthewson argue that selected effects play the key role in determining whether a state is pathological. In response, it is argued that a selected effects account faces a number of difficulties in light of modern genomic research. Firstly, a modern history approach to selection is problematic as a basis for assigning function to human traits in light of the small population sizes in the hominin lineage, which imply that selection has played a limited role in shaping (...) these genomes in the evolutionarily recent past. Secondly, determining both the genetic basis of disease and selective histories of the various alleles involved may be experimentally intractable. Thirdly, the existence of “selected disorders” is well supported, and yet on the other hand many other common diseases may not reduce evolutionary fitness. In summary, the biological ends promoted by natural selection, as best modeled in recent research, do not adequately ground a concept of dysfunction that aligns well with the interests of human health. (shrink)

Let us call the deliberate modification of an individual’s genome to improve it or its progeny intentional genetic enhancement. Governments are almost certain to require that any proposed intentional genetic enhancement of a human (IGEH) be tested first on (what researchers call) animal “models.” Intentional genetic enhancement of animals (IGEA), then, is an ambiguous concept because it could mean one of two very different things: an enhancement made for the sake of the animal’s own welfare, or an enhancement made for (...) the sake of satisfying a human desire. In either case, experimental procedures are likely to entail substantial risks to the experimental animals. What rules should govern IGEA? I criticize the abolitionist conclusions of animal rightists—that no IGEA should be permitted—and I criticize the permissive conclusions of speciesists—that all IGEA should be permitted. Both views are unsatisfying. I suggest instead that current animal welfare law provides a defensible platform on which to begin building ethically justifiable policy in this area. (shrink)

The origin of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is the subject of many hypotheses. One of them, proposed by Segreto and Deigin, assumes artificial chimeric construction of SARS‐CoV‐2 from a backbone of RaTG13‐like CoV and receptor binding domain (RBD) of a pangolin MP789‐like CoV, followed by serial cell or animal passage. Here we show that this hypothesis relies on incorrect or weak assumptions, and does not agree with the results of comparative genomics analysis. The genetic divergence between (...) SARS‐CoV‐2 and both its proposed ancestors is too high to have accumulated in a lab, given the timeframe of several years. Furthermore, comparative analysis of S‐protein gene sequences suggests that the RBD of SARS‐CoV‐2 probably represents an ancestral non‐recombinant variant. These and other arguments significantly weaken the hypothesis of a laboratory origin for SARS‐CoV‐2, while the hypothesis of a natural origin is consistent with all available genetic and experimental data. (shrink)

Recent experimental evidence suggests that most of the genome is transcribed into non‐coding RNAs. The initial transcripts undergo further processing generating shorter, metabolically stable RNAs with diverse functions. Small nucleolar RNAs (snoRNAs) are non‐coding RNAs that modify rRNAs, tRNAs, and snRNAs that were considered stable. We review evidence that snoRNAs undergo further processing. High‐throughput sequencing and RNase protection experiments showed widespread expression of snoRNA fragments, known as snoRNA‐derived RNAs (sdRNAs). Some sdRNAs resemble miRNAs, these can associate with argonaute proteins (...) and influence translation. Other sdRNAs are longer, form complexes with hnRNPs and influence gene expression. C/D box snoRNA fragmentation patterns are conserved across multiple cell types, suggesting a processing event, rather than degradation. The loss of expression from genetic loci that generate canonical snoRNAs and processed snoRNAs results in diseases, such as Prader‐Willi Syndrome, indicating possible physiological roles for processed snoRNAs. We propose that processed snoRNAs acquire new roles in gene expression and represent a new class of regulatory RNAs distinct from canonical snoRNAs.Also watch the Video Abstract. (shrink)

Developments in biotechnology and genomics have moved the issue of patenting scientific and technological inventions toward the center of interest. In particular, the patentability of genes of plants, animals, or humans and of genetically modified (parts of) living organisms has been discussed, and questioned, from various normative perspectives. This paper aims to contribute to this debate. For this purpose, it first explains a number of relevant aspects of the theory and practice of patenting. The focus is on a special (...) and increasingly significant type of patents, namely product patents. The paper provides three general arguments against the concept and practice of product patenting. The first argument briefly considers the claim that patents are legitimate because they promote socially useful innovation. Against this claim, it is argued that product patents may hamper rather than promote such innovation. The second and main argument concludes that product patents are not adequately based on actual technological inventions, as they should be according to the usual criteria of patentability. The principal moral issue is that product patents tend to reward patentees for inventions they have not really made available. The final argument proposes a method for patenting the heat of the sun. Assuming that granting this patent will be generally considered absurd, the argument exposes a further, fundamental problem of the concept and practice of product patenting. (shrink)

The first promising results from “streamlined,” minimal genomes tend to support the notion that these are a useful tool in biological systems engineering. However, compared with the speed with which genomic microbial sequencing has provided us with a wealth of data to study biological functions, it is a slow process. So far only a few projects have emerged whose synthetic ambition even remotely matches our analytic capabilities. Here, we survey current technologies converging into a future ability to engineer large‐scale biological (...) systems. We argue that the underlying synthetic technology, de novo DNA synthesis, is already rather mature – in particular relative to the scope of our current synthetic ambitions. Furthermore, technologies towards rationalizing the design of the newly synthesized DNA fragment are emerging. These include techniques to implement complex regulatory circuits, suites of parts on a DNA and RNA level to fine tune gene expression, and supporting computational tools. As such DNA fragments will, in most cases, be destined for operating in a cellular context, attention has to be paid to the potential interactions of the host with the functions encoded on the engineered DNA fragment. Here, the need of biological systems engineering to deal with a robust and predictable bacterial host coincides with current scientific efforts to theoretically and experimentally explore minimal bacterial genomes. (shrink)

Understanding the functional mechanisms underlying genetic signals associated with complex traits and common diseases, such as cancer, diabetes and Alzheimer's disease, is a formidable challenge. Many genetic signals discovered through genome‐wide association studies map to non‐protein coding sequences, where their molecular consequences are difficult to evaluate. This article summarizes concepts for the systematic interpretation of non‐coding genetic signals using genome annotation data sets in different cellular systems. We outline strategies for the global analysis of multiple association intervals and the in‐depth (...) molecular investigation of individual intervals. We highlight experimental techniques to validate candidate (potential causal) regulatory variants, with a focus on novel genome‐editing techniques including CRISPR/Cas9. These approaches are also applicable to low‐frequency and rare variants, which have become increasingly important in genomic studies of complex traits and diseases. There is a pressing need to translate genetic signals into biological mechanisms, leading to prognostic, diagnostic and therapeutic advances. (shrink)

Increasing European co-operation must take place in many areas, including medical ethics. Against the background of common cultural norms and pluralistic variation within political traditions, religion and lifestyles, Europe will have to converge towards unity within the field of medical ethics. This article examines how such convergence might develop with respect to four major areas: European research ethics committees, democratic health systems, the human genome project and rules for stopping futile treatments.

The concentration of low‐density lipoprotein (LDL) cholesterol (C) in plasma is a key determinant of cardiovascular disease risk and human genetic studies have long endeavoured to elucidate the pathways that regulate LDL metabolism. Massive genome‐wide association studies (GWASs) of common genetic variation associated with LDL‐C in the population have implicated SORT1 in LDL metabolism. Using experimental paradigms and standards appropriate for understanding the mechanisms by which common variants alter phenotypic expression, three recent publications have presented divergent and even contradictory (...) findings. Interestingly, although these reports each linked SORT1 to LDL metabolism, they did not agree on a mechanism to explain the association. Here, we review recent mechanistic studies of SORT1 – the first gene identified by GWAS as a determinant of plasma LDL‐C to be evaluated mechanistically. (shrink)

Genomic research projects that collect tissues from deceased organ and tissue donors must obtain the authorization of family decision makers under difficult circumstances that may affect the authorization process. Using a quasi-experimental design, the Ethical, Legal, and Social Issues (ELSI) substudy of the Genotype-Tissue Expression (GTEx) project compared the recall and understanding of the donation authorization process of two groups: family members who had authorized donation of tissues to the GTEx project (the comparison group) and family members who had (...) authorized organ and tissue donations in years previous, who subsequently participated in two different mock-authorization processes that mimicked the GTEx authorization process (the intervention groups). Participants in the comparison and intervention groups were matched on key demographic characteristics.We found that participants in the intervention groups who experienced a mock-authorization process demonstrated better recall of the tissue donation request than members of the comparison group. Our data indicate that the stress associated with the loss of a loved one limited the ability of family members to recall details about the GTEx project. However, we found a similar lack of knowledge in both the comparison and the intervention group participants, suggesting lack of knowledge may be due to the complexity and unfamiliarity of the information presented to them during the authorization process. We discuss these findings in the context of everyday clinical decision making in cognitively challenging conditions. (shrink)

Recent experimental data from proteomics and genomics are interpreted here in ways that challenge the predominant viewpoint in biology according to which the four evolutionary processes, including mutation, recombination, natural selection and genetic drift, are sufficient to explain the origination of species. The predominant viewpoint appears incompatible with the finding that the sequenced genome of each species contains hundreds, or even thousands, of unique genes - the genes that are not shared with any other species. These unique genes (...) and proteins, singletons, define the very character of every species. Moreover, the distribution of protein families from the sequenced genomes indicates that the complexity of genomes grows in a manner different from that of self-organizing networks: the dominance of singletons leads to the conclusion that in living organisms a most unlikely phenomenon can be the most common one. In order to provide proper rationale for these conclusions related to the singletons, the paper first treats the frequency of functional proteins among random sequences, followed by a discussion on the protein structure space, and it ends by questioning the idea that protein domains represent conserved units of evolution. (shrink)

The analysis of genetic and epigenetic mechanisms of the genotype–phenotypic connection has, so far, only been possible in a handful of genetic model systems. Recent technological advances, including next‐generation sequencing methods such as RNA‐seq, ChIP‐seq and RAD‐seq, and genome‐editing approaches including CRISPR‐Cas, now permit to address these fundamental questions of biology also in organisms that have been studied in their natural habitats. We provide an overview of the benefits and drawbacks of these novel techniques and experimental approaches that can (...) now be applied to ecological and evolutionary vertebrate models such as sticklebacks and cichlid fish. We can anticipate that these new methods will increase the understanding of the genetic and epigenetic factors influencing adaptations and phenotypic variation in ecological settings. These new arrows in the methodological quiver of ecologist will drastically increase the understanding of the genetic basis of adaptive traits – leading to a further closing of the genotype–phenotype gap. -/- . (shrink)

Current work in experimental biology revolves around a handful of animal species. Studying only a few organisms limits science to the answers that those organisms can provide. Nature has given us an overwhelming diversity of animals to study, and recent technological advances have greatly accelerated the ability to generate genetic and genomic tools to develop model organisms for research on host–microbe interactions. With the help of such models the authors therefore hope to construct a more complete picture of the (...) mechanisms that underlie crucial interactions in a given metaorganism (entity consisting of a eukaryotic host with all its associated microbial partners). As reviewed here, new knowledge of the diversity of host–microbe interactions found across the animal kingdom will provide new insights into how animals develop, evolve, and succumb to the disease. (shrink)

The computational genomics community has come increasingly to rely on the methodology of creating annotations of scientific literature using terms from controlled structured vocabularies such as the Gene Ontology (GO). We here address the question of what such annotations signify and of how they are created by working biologists. Our goal is to promote a better understanding of how the results of experiments are captured in annotations in the hope that this will lead to better representations of biological reality (...) through both the annotation process and ontology development, and in more informed use of the GO resources by experimental scientists. (shrink)

The genetic code appeared on Earth at the origin of life, and the codes of culture arrived almost four billion years later. For a long time it has been assumed that these are the only codes that exist in Nature, and if that were true we would have to conclude that codes are extraordinary exceptions that appeared only at the beginning and at the end of the history of life. In reality, various other organic codes have been discovered in the (...) past few decades and it is likely that more will come to light in the future. The existence of many organic codes in Nature is therefore an experimental fact, but also more than that. It is one of those facts that have extraordinary implications. In this book it is shown that the genetic code was a precondition for the origin of the first cells, the signal transduction codes divided the first cells into three primary kingdoms (Archaea, Bacteria and Eukarya), the splicing codes were instrumental to the origin of the eukaryotic nucleus, the histone code provided a new regulation system in eukaryotic genomes, and the cytoskeleton codes allowed the Eukarya to perform internal movements, including those of mitosis and meiosis. It is shown, furthermore, that organic codes had a key role in multicellular life, in particular in the origin of animals, the origin of mind and the origin of language. The great events of macroevolution, in other words, were associated with the appearance of new organic codes, and we can easily understand why. The reason is that a new code brings into existence something that has never existed before because it creates arbitrary associations, relationships that are not determined by physical necessity. Another outstanding implication is the fact that codes involve meaning and we need therefore to introduce in biology, with the standard methods of science, not only the concept of biological information but also that of biological meaning. The research on biological codes, in conclusion, is bringing to light new mechanisms in evolution and new fundamental concepts in science. This research is the field of Code Biology, the study of all codes of life, from the genetic code to the codes of culture, from the origin of life to the origin of man. (shrink)

Although neither the genome nor the environment can be manipulated in research on human behaviour, some of the new tools of molecular genetics can be brought to bear on human behavioural disorders (e.g. cognitive disabilities) and quantitative traits (e.g. cognitive abilities). The inability to manipulate the human genome experimentally has had the positive effect of focusing attention on naturally occuring genetic variation responsible for behavioural differences among individuals in all their complex multifactorial splendour. Genes in such complex multiple‐gene systems are (...) called quantitative trait loci (QTLs), which merge the two worlds of genetic research, quantitative genetics and molecular genetics. Although most genetic research on complex human behaviour has focused on severe mental disorders, cognitive abilities and disabilities may be even more immediately relevant to neuroscience. For example, verbal ability and spatial ability are two of the most heritable cognitive abilities, and reading disability is the first behavioural disability for which replicated QTL linkage has been found. The purpose of this essay is to provide an overview of the genetics of cognitive abilities and disabilities as an example of the impending merger of quantitative genetics and molecular genetics in QTL analysis of complex traits. (shrink)

The “Human Genome Project” was completed in 2003, shifting the focus to proteome and transcriptome research. One approach to proteomics involves the comprehensive visualization of the localization of proteins in all tissues and organs. We discuss in situ phospho‐protein atlases, which are systematized representations of the localization of proteins. Protein atlases provide important information about the identity and presence of proteins in specific organs, tissues and cells under physiological and pathological conditions. Antibody‐based immunohistochemical analysis is a powerful method for generating (...) a protein atlas. However, it is difficult to localize phosphorylated proteins under in vivo physiological conditions, even with immunohistochemistry, because these proteins tend to be dephosphorylated or phosphorylated due to the experimental manipulations. We also discuss an improved immunohistochemical method for precisely detecting phosphorylated protein, using the detection of phosphorylated ERK1/2 as an example. We consider that it is possible and useful to generate a phospho‐protein atlas. (shrink)