Animal cloning by nuclear transfer: state-of-the-art and future perspectives

Model organisms are essential to study the genetic basis of human diseases. Transgenic mammalian models, especially genetic knock-out mice have catalysed the progress in this area. To continue the advancement, further sophisticated and refined models are crucially needed to study the genetic basis and manifestations of numerous human diseases. Coinciding with the start of the new era of post-genomic research, new tools for establishment of transgenesis, such as nuclear transfer and gene targeting in somatic cells, have become available, offering a unique opportunity for the generation of transgenic animal models. The new technology provides important tools for comparative functional genomics to promote the interpretation and increase the practical value of the data generated in numerous mouse models. This paper discusses the state-of-the-art of the nuclear replacement technology and presents future perspectives.     

The ethics of functional genomics: same, same, but different?

Respect for human life--a notion of worth uniting all members of the human race--constitutes a sense of anthropocentrism that has long been the justification for the enrollment of animals in experimentation executed to develop therapies to alleviate human suffering. Currently, however, advances in functional genomics are causing a qualitative transformation of the rationale for medical research performed on animals. The notion of human distinctness is being fundamentally challenged when gene sequences similar to those found in humans are identified in different species. In this Opinion article, we would like to highlight an inherent tension brought about by the current developments in functional genomics: a tension between the scientific and the ethical status of gene sequences. Is it reasonable to argue that they are the same for all practical purposes but different in ethical status?     

A human rights approach to an international code of conduct for genomic and clinical data sharing

Fostering data sharing is a scientific and ethical imperative. Health gains can be achieved more comprehensively and quickly by combining large, information-rich datasets from across conventionally siloed disciplines and geographic areas. While collaboration for data sharing is increasingly embraced by policymakers and the international biomedical community, we lack a common ethical and legal framework to connect regulators, funders, consortia, and research projects so as to facilitate genomic and clinical data linkage, global science collaboration, and responsible research conduct. Governance tools can be used to responsibly steer the sharing of data for proper stewardship of research discovery, genomics research resources, and their clinical applications. In this article, we propose that an international code of conduct be designed to enable global genomic and clinical data sharing for biomedical research. To give this proposed code universal application and accountability, however, we propose to position it within a human rights framework. This proposition is not without precedent: international treaties have long recognized that everyone has a right to the benefits of scientific progress and its applications, and a right to the protection of the moral and material interests resulting from scientific productions. It is time to apply these twin rights to internationally collaborative genomic and clinical data sharing.     

Natural compounds as a source of protein tyrosine phosphatase inhibitors: application to the rational design of small-molecule derivatives

Reversible phosphorylation of tyrosine residues is a key regulatory mechanism for numerous cellular events. Protein tyrosine kinases and protein tyrosine phosphatases (PTPs) have a pivotal role in regulating both normal cell physiology and pathophysiology. Accordingly, deregulated activity of both protein tyrosine kinases and PTPs is involved in the development of numerous congenitically inherited and acquired human diseases, prompting obvious pharmaceutical and academic research interest. The development of compound libraries with higher selective PTP inhibitory activity has been bolstered by the realization that many natural products have such activity and thus are interesting biologically lead compounds, which properties are widely exploited. In addition, more rational approaches have focused on the incorporation of phosphotyrosine mimetics into specific peptide templates (peptidomimetic backbones). Additional factors furthering discovery as well as therapeutic application of new bioactive molecules are the integration of functional genomics, cell biology, structural biology, drug design, molecular screening and chemical diversity. Together, all these factors will lead to new avenues to treat clinical disease based on PTP inhibition.     

Public consultation in ethics an experiment in representative ethics

Genome Canada has funded a research project to evaluate the usefulness of different forms of ethical analysis for assessing the moral weight of public opinion in the governance of genomics. This paper will describe a role of public consultation for ethical analysis and a contribution of ethical analysis to public consultation and the governance of genomics/biotechnology. Public consultation increases the robustness of ethical analysis with a more diverse set of moral experiences. Consultation must be carefully and respectfully designed to generate sufficiently diverse and rich accounts of moral experiences. Since dominant groups tend to define ethical or policy issues in a manner that excludes some interests or perspectives, it is important to identify the range of interests that diverse publics hold before defining the issue and scope of the discussion and the premature foreclosure of ethical dialogue. Consequently, a significant contribution of ethical dialogue strengthened by social analysis is to consider the context and non-policy use of power to govern genomics and to sustain social debate on enduring ethical issues.     

Genomic Studies of Hereditary Disorders and the Genetic Diversity of Siberian Populations

The review considers the results of genome research on the Russian program Human Genome carried out in the Institute of Medical Genetics (Tomsk) since 1990. The three major fields were molecular cytogenetics and chromosomal disorders, genomics of Mendelian and common diseases, and ethnogenomics of the North Asian population. Several human genes were cytogenetically mapped, and numerical and structural abnormalities associated with human diseases were studied by fluorescence hybridization. Procedures of DNA diagnosis were developed for 15 hereditary diseases. New data were obtained on the genetic heterogeneity of idiopathic hypertrophic cardiomyopathy. The genetic bases of multifactorial (atopic bronchial asthma) and infectious (tuberculosis) diseases were analyzed. The North Eurasian population (41 local populations of 21 ethnic groups) was tested for genetic diversity with numerous genetic markers, including Y-chromosomal haplotypes, autosomal microsatellites, and polymorphic Alu insertions.     

Genomic study of the hereditary pathology and genetic diversity of the Siberian population

The review considers the results of genome research on the Russian program Human Genome carried out in the Institute of Medical Genetics (Tomsk) from 1990. The three major fields were molecular cytogenetics and chromosomal disorders, genomics of Mendelian and high-incidence diseases, and ethnogenomics of the North Asian population. Several human genes were cytogenetically mapped, and numerical and structural abnormalities associated with human diseases studied by fluorescence hybridization. Procedures of DNA diagnostics were developed for 15 hereditary diseases. New data were obtained on genetic heterogeneity of idiopathic hypertrophic cardiomyopathy. The genetic bases of multifactorial (atopic bronchial asthma) and infectious (tuberculosis) diseases were analyzed. The North Eurasian population (41 local populations of 21 ethnic groups) was tested for genetic diversity with numerous genetic markers, including Y-chromosomal haplotypes, autosomal microsatellites, and polymorphic Alu insertions.     

Molecular Cytogenetics and Cytogenomics of Brain Diseases

Molecular cytogenetics is a promising field of biomedical research that has recently revolutionized our thinking on genome structure and behavior. This is in part due to discoveries of human genomic variations and their contribution to biodiversity and disease. Since these studies were primarily targeted at variation of the genome structure, it appears apposite to cover them by molecular cytogenomics. Human brain diseases, which encompass pathogenic conditions from severe neurodegenerative diseases and major psychiatric disorders to brain tumors, are a heavy burden for the patients and their relatives. It has been suggested that most of them, if not all, are of genetic nature and several recent studies have supported the hypothesis assuming them to be associated with genomic instabilities (i.e. single-gene mutations, gross and subtle chromosome imbalances, aneuploidy). The present review is focused on the intriguing relationship between genomic instability and human brain diseases. Looking through the data, we were able to conclude that both interindividual and intercellular genomic variations could be pathogenic representing, therefore, a possible mechanism for human brain malfunctioning. Nevertheless, there are still numerous gaps in our knowledge concerning the link between genomic variations and brain diseases, which, hopefully, will be filled by forthcoming studies. In this light, the present review considers perspectives of this dynamically developing field of neurogenetics and genomics.     

Genomics research in the UK--the social science agenda

We sketch the development of UK genetics and genomics research, and emphasize the UK's key role in the international genetics and genomics research community. We highlight in particular the part played by the UK's Research Councils and other funders. With the move from genomics to post-genomics research, the field is diversifying, and interdisciplinarity becomes increasingly important, as traditional disciplinary boundaries become blurred, or break down, in the face of newly emerging sciences. We consider the changing nature of health and ill health in the developed and developing world, and questions about the complex nature of the relationships between genes and the environment, and their future implications for human health and human populations. We describe the ESRC's activities, stressing the importance of both the social, ethical and legal issues raised by these emerging disciplines, and of public engagement. Finally, we link the data handling and analysis issues raised by these emerging sciences, with other new research areas, in particular the UK's e-Science programme.     

Ethical priority of the most actionable system of biomolecules: the metabolome

The metabolome is a system of small biomolecules (metabolites) and a direct result of human bioculture. Consequently, metabolomics is well poised to impact anthropological and biomedical research for the foreseeable future. Overall, we provide a perspective on the ethical, legal, and social implications (ELSI) of metabolomics, which we argue are often more alarming than those of genomics. Given the current mechanisms to fund research, ELSI beyond human DNA is stifled and in need of considerable attention.     

Closing the Gap between Knowledge and Clinical Application: Challenges for Genomic Translation

Despite early predictions and rapid progress in research, the introduction of personal genomics into clinical practice has been slow. Several factors contribute to this translational gap between knowledge and clinical application. The evidence available to support genetic test use is often limited, and implementation of new testing programs can be challenging. In addition, the heterogeneity of genomic risk information points to the need for strategies to select and deliver the information most appropriate for particular clinical needs. Accomplishing these tasks also requires recognition that some expectations for personal genomics are unrealistic, notably expectations concerning the clinical utility of genomic risk assessment for common complex diseases. Efforts are needed to improve the body of evidence addressing clinical outcomes for genomics, apply implementation science to personal genomics, and develop realistic goals for genomic risk assessment. In addition, translational research should emphasize the broader benefits of genomic knowledge, including applications of genomic research that provide clinical benefit outside the context of personal genomic risk.     

Memory enhancement: the progress and our fears

In a recent article Rose (2002) raises numerous crucial issues with regard to the research into and the use of cognition or memory enhancing agents. Although development of 'smart' drugs is in its infancy, his paper delineates some issues society may have to face when these drugs arrive. Questions about the development of such drugs may be interesting to several readers of Genes Brain and Behavior given the wealth of information expected to be gained on brain function from studies using genetic approaches including mutagenesis, transgenic techniques and genomics in general. Besides the scientific questions, several ethical issues may need to be addressed that are of interest to us all. Rose (2002 ) discusses some of these questions, but perhaps presents a too negative view on the problems, especially with regard to the present and future of memory research. This paper is intended to focus mainly on the scientific questions and argues that our fear of complex ethical problems should not make us throw the baby (i.e., our research and discoveries) out with the bath water.     

Human genome project: pharmacogenomics and drug development

Now that all 30,000 or so genes that make up the human genome have been deciphered, pharmaceutical industries are emerging to capitalize the custom based drug treatment. Understanding human genetic variation promises to have a great impact on our ability to uncover the cause of individual variation in response to therapeutics. The study of association between genetics and drug response is called pharmacogenomics. The potential implication of genomics and pharmacogenomics in clinical research and clinical medicine is that disease could be treated according to the interindividual differences in drug disposition and effects, thereby enhancing the drug discovery and providing a stronger scientific basis of each patient's genetic constitution. Sequence information derived from the genomes of many individuals is leading to the rapid discovery of single nucleotide polymorphisms or SNPs. Detection of these human polymorphisms will fuel the discipline of pharmacogenomics by developing more personalized drug therapies. A greater understanding of the way in which individuals with a particular genotype respond to a drug allows manufacturers to identify population subgroups that will benefit most from a particular drug. The increasing emphasis on pharmacogenomics is likely to raise ethical and legal questions regarding, among other things, the design of research studies, the construction of clinical trials and the pricing of drugs.     

Ethical and legal implications of pharmacogenomics

Pharmacogenomics is the application of genomics technology to the discovery and development of drugs. A greater understanding of the way in which individuals with a particular genotype respond to a drug allows manufacturers to identify population subgroups that will benefit most from a particular drug. The increasing emphasis on pharmacogenomics is likely to raise ethical and legal questions regarding, among other things, the design of research studies, the construction of clinical trials and the pricing of drugs.     

Genomics research in the UK—the social science agenda

Abstract

We sketch the development of UK genetics and genomics research, and emphasize the UK's key role in the international genetics and genomics research community. We highlight in particular the part played by the UK's Research Councils and other funders. With the move from genomics to post-genomics research, the field is diversifying, and interdisciplinarity becomes increasingly important, as traditional disciplinary boundaries become blurred, or break down, in the face of newly emerging sciences. We consider the changing nature of health and ill health in the developed and developing world, and questions about the complex nature of the relationships between genes and the environment, and their future implications for human health and human populations. We describe the ESRC's activities, stressing the importance of both the social, ethical and legal issues raised by these emerging disciplines, and of public engagement. Finally, we link the data handling and analysis issues raised by these emerging sciences, with other new research areas, in particular the UK's e-Science programme.     

生物样本库及其伦理问题简介

随着分子和基因组信息对流行病学影响的增加,无数遗传流行病学研究和后人类基因组计划的研究都越来越依赖人类生物样本库的使用。生物样本库的范围也已横跨学术或者医院环境下的小数量收集到大规模的全国性储藏。尽管生物样本库的概念并不新,但是在基因组研究和后人类基因组计划的背景下,伴随它们十几年极大发展的是无数待解决的伦理挑战。从生物样本库的概念着手,介绍了其与一般遗传数据库的区别以及建立生物样本库的意义;然后介绍并比较国际上已有的生物样本库,以及其伦理问题和伦理法律框架的发展趋势。     

Dissecting complex phenotypes using the genomics of twins

Genetics in the post-genomic period is shifting from structural to functional genetics or genomics. Meanwhile, the use of twins is largely expanding from traditional heritability estimation for disease phenotypes to the study of both diseases and various molecular phenotypes, such as the regulatory phenotypes in functional genomics concerning gene expression and regulation, by engaging both classical twin design and marker-based gene mapping techniques in genetic epidemiology. New research designs have been proposed for making novel uses of twins in studying the molecular basis in the epigenetics of human diseases. Besides, twins not only serve as ideal samples for disease gene mapping using conventional genetic markers but also represent an excellent model for associating DNA copy number variations, a structural genetic marker, with human diseases. It is believed that, with the rapid development in biotechniques and new advances in bioinformatics, the unique samples of twins will make new contributions to our understanding of the nature and nurture in complex disease development and in human health. This paper aims at summarizing the new uses of twins in current genetic studies and suggesting novel proposes together with useful design and analytical strategies.     

Publics and vaccinomics: beyond public understanding of science

Vaccines have been among the most effective tools for addressing global public health challenges. With the advent of genomics, novel approaches for vaccine discovery are opening up new opportunities for vaccine development and applications, particularly with the expectation of personalized vaccines and the possibility of addressing a broader range of infectious diseases. In this context, it is useful to reflect on the social contexts of vaccine development as these have been influenced by social, ethical, political challenges. This article discusses the historical context of vaccine controversies and factors that help explain public acceptance and resistance, illustrating that these challenges go well beyond simple public misunderstandings. The broader vaccine challenges evident along the innovation trajectory, from development to commercialization and implementation include problems in research and development, organizational issues, and legal and regulatory challenges that may collectively contribute to public resistance or confidence. The recent history of genomics provides further lessons that the developing field of vaccinomics can learn from.     

Ethical issues and GenomEUtwin.

The post-genomic era is witnessing a proliferation of large-scale and population based genetic and genomic research projects. Many countries have or are establishing research biobanks and, as with GenomEUtwin, there is great interest in building multinational projects that link genotypic and phenotypic information from different centers. Clearly, the conduct of these projects raises multiple ethical issues, and the knowledge generated will continually recast the ethical, legal and social implications (ELSI) of such research. Maximising the scientific profit from this work while minimizing the risks to the participants requires full integration of ethics components into the structure and functioning of these projects. GenomEUtwin is organized around five intellectual cores, including an Ethics Core which operates across the entire project. This paper describes the role of the Ethics Core and presents an overview of the guidelines on which the principles followed in GenomEUtwin are based. We outline the major ethical concerns of our project and highlight complexities arising from diverse national legislations. Finally, the role of empirically based ethics research is discussed for understanding the ethical, legal, social and economic implications of human genetics and genomics research.     

Educating health-care professionals about genetics and genomics

To biomedical researchers, this is the 'genome era'. Advances in genetics and genomics such as the sequence of the human genome, the human haplotype map, open access databases, cheaper genotyping and chemical genomics have already transformed basic and translational biomedical research. However, for most clinicians, the genome era has not yet arrived. For genomics to have an effect on clinical practice that is comparable to its impact on research will require advances in the genomic literacy of health-care providers. Here we describe the knowledge, skills and attitudes that genomic medicine will require, and approaches to integrate them into the health-care community.