Germline Gene Modification Research Articles

Ethical issues raised by intergenerational monitoring in clinical trials of germline gene modification

As research involving gene editing continues to advance, we are headed in the direction of being able to modify the human germline. Should we reach a point where an argument...

Ethical issues in human germline gene editing: a perspective from China.

The ethical issues associated with germline gene modification and embryo research are some of the most contentious in current international science policy debates. In this paper, we argue that new genetic techniques, such as CRISPR, demonstrate that there is an urgent need for China to develop its own regulatory and ethical framework governing new developments in genetic and embryo research. While China has in place a regulatory framework, it needs to be strengthened to include better compliance oversight and explicit criteria for how different types of research should be reviewed by regulatory authorities. We also document a variety of opinions about the new technologies among the public, scholars, and policy makers. China needs to develop its own regulations in coordination with other countries; but it is unlikely that an international consensus will be achieved in this area, given the existing differences in regulations between countries. We should aim at harmonization, not necessarily complete consensus, and the perspective from China is vital when international norms are developed and harmonized. Chinese policy makers and researchers need to be aware of the international discussions, at the same time as the international community is aware of, and accommodates, Chinese positions on important policy options.

Raising the Virtuous Bar: The Underlying Issues of Genetic Moral Enhancement

ABSTRACTFrom the perspective of virtue ethics, is it possible and permissible to enhance moral behavior through gene modification? In preparation to answer this question, we must ask five questions: (1) What may we assume regarding genetic inheritance and human nature? (2) Can specific genes predispose behavior related to the moral virtues? (3) What kind of genetic enhancement would be useful for moral enhancement? (4) Should there be a distinction between somatic and germline gene modification? (5) Is genetic modification best approach to moral enhancement? This article concedes that genetic engineering has the capacity to enhance the human disposition to moral behavior, but gene editing cannot create virtue because virtues are stable, habituated dispositions, acquired over time. That being said, gene editing for purposes of enhancing moral behavior is permissible.

Counterpoint: The Potential Harms of Human Gene Editing Using CRISPR-Cas9.

The anticipated benefits of human gene editing with the use of CRISPR (clustered interspaced short palindromic repeats)-Cas9 are both familiar and contested. First and foremost is the expectation of cures for blood disorders, lung diseases, cancers, and other maladies as clinician-scientists master various insertion, disruption, and deletion techniques. In addition to these potential therapeutic benefits, for some, there are the potential benefits of human enhancement as investigators learn to modify specific genetic traits in an effort to improve healthy individuals. Importantly, these proximate and distant potential benefits might be obtained through somatic cell or germ line gene modification. With germ line gene modification (which involves inserting, deleting, or replacing the DNA of human sperm, eggs, or embryos), there is the added potential benefit that changes made to the human genome (especially those aimed at correcting disease-causing and sometimes life-limiting genetic mutations) will be inherited by future generations. This would obviate the need for repeat somatic cell modifications from one generation to the next. The potential benefits of gene editing, however, are neither guaranteed nor risk-free. The potential harms include off-target changes (as might happen with the inactivation of essential genes), the inappropriate activation of cancer-causing genes, and the rearrangement of chromosomes. Additionally, there are the risks of on-target changes with unintended consequences, the creation of mosaics of altered and unaltered cells, and the introduction of changes that generate an immune response. In addition to these potential medical harms, there are also potential social harms. There is, for example, the risk that the introduction and eventual wide utilization of gene editing technology will exacerbate existing inequalities resulting in human rights abuses, a new wave of eugenics, increased discrimination and increased stigmatization. As such, the overarching risks with human gene editing by use of CRISPR-Cas9 are two-fold. First, there is the risk …

Germline Editing: Editors Cautionary.

This communication is regarding the recent editing of the genome of the human embryo with CRISPR/Cas9 which generated a debate amongst the biological scientists around the world. Editing human germline genes may act as godsend in some serious genetic and other disorders as the genes related to these disorders can be replaced effectively. The scientists are in dilemma whether the human germline gene modification is a boon or bane for the human society. Though editing human germline genes may be an answer to many serious genetic disorders however; it may have unpredictable effects on future generations. The ethical issues regarding the germline editing need further discussion which may have implications on human race and on-going human evolution. Thus, the researchers need to be doubly cautious and some stringent regulations should be framed regarding the various aspects of germ line gene modifications and any potential conflict with nature for future outcome.

UK's Legalisation of Mitochondrial Donation in IVF Treatment: A Challenge to the International Community or a Promotion of Life-saving Medical Innovation to Be Followed by Others?

Mitochondrial DNA diseases are rare genetic disorders, which can have a devastating effect on the patients' health and well-being. There is no cure for such diseases, although recent experiments suggest that there may be a way to prevent them by genetically altering the eggs or embryos through a procedure known as mitochondrial donation. However, such a procedure not only raises serious safety and ethical concerns, but legal challenges as well, since it involves germline gene modification, which until recently was not legal in the UK or elsewhere. In February 2015, the British Parliament amended the relevant legislation to allow such. a procedure, making the UK the first state to openly challenge the global policy on germline gene modification. The article presents the scientific background to the procedure and discusses the regulatory challenges brought by the first case of its legalisation.

Biotechnology. A prudent path forward for genomic engineering and germline gene modification.

A framework for open discourse on the use of CRISPR-Cas9 technology to manipulate the human genome is urgently needed

Potential impact of human mitochondrial replacement on global policy regarding germline gene modification

Previous discussions regarding human germline gene modification led to a global consensus that no germline should undergo genetic modification. However, the UK Human Fertilisation and Embryology Authority, having conducted at the UK Government’s request a scientific review and a wide public consultation, provided advice to the Government on the pros and cons of Parliament’s lifting a ban on altering mitochondrial DNA content of human oocytes and embryos, so as to permit the prevention of maternal transmission of mitochondrial diseases. In this commentary, relevant ethical and biomedical issues are examined and requirements for proceeding with this novel procedure are suggested. Additionally, potentially significant impacts of the UK legalization on global policy concerning germline gene modification are discussed in the context of recent advances in genome-editing technology. It is concluded that international harmonization is needed, as well as further ethical and practical consideration, prior to the legalization of human mitochondrial replacement.

International regulatory landscape and integration of corrective genome editing into in vitro fertilization.

Genome editing technology, including zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeat (CRISPR)/Cas, has enabled far more efficient genetic engineering even in non-human primates. This biotechnology is more likely to develop into medicine for preventing a genetic disease if corrective genome editing is integrated into assisted reproductive technology, represented by in vitro fertilization. Although rapid advances in genome editing are expected to make germline gene correction feasible in a clinical setting, there are many issues that still need to be addressed before this could occur. We herein examine current status of genome editing in mammalian embryonic stem cells and zygotes and discuss potential issues in the international regulatory landscape regarding human germline gene modification. Moreover, we address some ethical and social issues that would be raised when each country considers whether genome editing-mediated germline gene correction for preventive medicine should be permitted.Electronic supplementary materialThe online version of this article (doi:10.1186/1477-7827-12-108) contains supplementary material, which is available to authorized users.

A TALE of Two Nucleases: Gene Targeting for the Masses?

Genome editing appears poised to enter an exciting new era. Targeted double-stranded breaks due to custom restriction enzymes are powerful nucleating events for the induction of local changes in the genome. The zinc finger nuclease (ZFN) platform established the potential of this approach for the zebrafish, but access to high quality reagents has been a major bottleneck for the field. However, two groups recently report successful somatic and germline gene modification using a new nuclease architecture, transcription activator-like effector nucleases (TALENs). TALEN construction is simpler, potentially more reliable, and in the few cases examined, shows fewer off-target effects than corresponding ZFNs. TALENs promise to bring gene targeting to the majority of zebrafish laboratories.

PSCDGs of mouse multipotent adult germline stem cells can enter and progress through meiosis to form haploid male germ cells in vitro

Spermatogonial stem cells (SSCs) provide the basis for spermatogenesis throughout adult life by undergoing self-renewal and differentiation into sperm. SSC-derived cell lines called multipotent adult germline stem cells (maGSCs) were recently shown to be pluripotent and to have the same potential as embryonic stem cells (ESCs). In a differentiation protocol using retinoic acid (RA) and based on a double selection strategy, we have shown that ESCs are able to undergo meiosis and produce haploid male germ cells in vitro. Using this differentiation protocol we have now succeeded to generate haploid male germ cells from maGSCs in vitro. maGSCs derived from a Stra8-EGFP transgenic mouse line were differentiated into stable spermatogonial stages and further cultured. These cells were transfected with a postmeiotic specific promoter construct Prm1-DsRed to monitor retinoic acid (RA) induced differentiation into haploid male gametes. Our protocol is another approach for the production of pluripotent stem cell derived gametes (PSCDGs) and is an alternative for the investigation of mammalian spermatogenesis, germ line gene modification and epigenetic reprogramming. If reproducible with pluripotent cell lines derived from human SSCs, it could also be used as a therapeutic approach for the treatment of male infertility.

Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment

Most genetically engineered mouse (GEM) models for colon cancer are based on tissuewide or germline gene modification, resulting in tumors predominantly of the small intestine. Several of these models involve modification of the adenomatous polyposis coli (Apc) gene and are excellent models for familial cancer predisposition syndromes. We have developed a stochastic somatic mutation model for sporadic colon cancer that presents with isolated primary tumors in the distal colon and recapitulates the entire adenoma-carcinoma-metastasis axis seen in human colon cancer. Using this model, we have analyzed tumors that are either solely mutant in the Apc gene or in combination with another colon cancer-associated mutant gene, the Kras G12D allele. Because of the restricted location in the distal colon, the natural history of the tumors can be analyzed by serial colonoscopy. As the mammalian target of rapamycin (mTOR) pathway is a critical component of the complex signaling network in colon cancer, we used this model to assess the efficacy of mTOR blockade through rapamycin treatment of mice with established tumors. After treatment, Apc mutant tumors were more than 80% smaller than control tumors. However, tumors that possessed both Apc and Kras mutations did not respond to rapamycin treatment. These studies suggest that mTOR inhibitors should be further explored as potential colorectal cancer therapies in patients whose tumors do not have activating mutations in KRAS.

373. A General System for Germline Gene Modification in Vertebrates

373. A General System for Germline Gene Modification in Vertebrates

Re-interpreting some common objections to three transgenic applications: GM foods, xenotransplantation and germ line gene modification (GLGM)

Concerns about safety to the individual, the wider community and the potential impact on the environment are typical consequentialist objections to transgenesis that feature prominently in public debates about its ethical acceptability. I consider some of these claims with respect to their motivation, validity and their overall influence on public policy using three well-discussed applications of transgenesis: GM foods, xenotransplantation and germ line gene modification (GLGM).

Homing efficiency and proliferation kinetics of male germ line stem cells following transplantation in mice.

Stem cells in the male germ line (spermatogonial stem cells [SSCs]) are an important target for male fertility restoration and germ line gene modification. To establish a model system to study the biology and the applications of SSCs in mice, I used a sequential transplantation strategy to analyze the process by which SSCs colonize the stem cell niche after transplantation and to determine the efficiency of the process (homing efficiency). I further analyzed the proliferation kinetics of SSCs after colonization. The number of SSCs gradually decreased during the homing process, and only 12% of SSCs successfully colonized the niche on Day 7 after transplantation, but the number of SSCs increased by Day 14. Thus, homing efficiency of adult mouse SSCs is 12%. These results indicate that SSCs are rapidly lost upon transplantation and require approximately 1 wk to settle into their niches before initiating expansion. Using this SSC homing efficiency, I calculated that approximately 3000 SSCs exist in one normal adult testis, representing approximately 0.01% of total testis cells. Between 7 days and 1 mo after transplantation, SSCs proliferated 7.5-fold. However, they did not significantly proliferate thereafter until 2 mo, and only 8 SSCs supported one colony of donor-derived spermatogenesis from 1 to 2 mo. These results suggest that self-renewal and differentiation of SSCs are strictly regulated in coordination with the progress of an entire unit of regenerating spermatogenesis.

Shaping individuality: human inheritable germ line gene modification.

In this paper I deal with ethical factors surrounding germline gene therapy. Such implications include intergenerational responsibility, human dignity, moral status of embryos and so on. I will explore the relevance of the above mentioned issues to discuss the ethical implication of human germline gene therapy (HGLT). We will see that most of arguments claimed by bioethicists do not provide valid reason to oppose HGLT. I will propose an alternative view, based on personal identity issues, to discuss the ethics of human inheritable gene modification.

Human Pluripotential Stem Cells

After completing this article, readers should be able to: 1. List the three cells from which mouse pluripotential stem cells can be derived. 2. List the types of specific cells that have been differentiated from murine embryonic stem cells in laboratory investigations. 3. Delineate the potential methods of using human stem cells to minimize immunologic rejection after transplantation. 4. Describe some of the issues requiring resolution before human stem cells can be used in therapies. The dream of one day being able to provide an unlimited supply of human tissues for transplantation came one step closer 2 years ago when two teams of scientists from Johns Hopkins University and the University of Wisconsin announced the successful derivation of human pluripotential stem cells (PSCs). This research immediately caught the public’s eye because of its enormous impact on transplantation therapies and the sources of tissues. Human stem cells are renewable in culture and are capable of differentiating into a wide variety of tissue types. The unlimited ability to divide and the capability to form into almost every cell type provide the source of replacement cells for transplantation and raise the hopes of numerous patients who have debilitating conditions, such as Parkinson disease, Alzheimer disease, stroke, and type I diabetes. Human stem cells will be important for in vitro studies of human gene discovery, for pharmaceutical research such as drug toxicology studies for screening and testing, and as a renewable source of cells for tissue transplantation and gene therapies. In addition to clinical applications, human stem cells provide a powerful tool for biomedical research into human embryogenesis, specific gene functions, and lineage development. PSCs, primarily embryonic stem (ES) cells, have been used extensively in studies of embryogenesis, gene function, and development in the mouse. Present in the early stages of embryo development, PSCs can generate all of …

Human germline gene modification: a dissent

Human germline gene modification has been foreseen but not yet accomplished.1–6 It can be defined as the genetic manipulation of human germ cells, or of a conceptus, resulting in inherited changes in DNA. With the development of advanced in-vitro fertilisation (IVF) methods, preimplantation DNA analysis, improved techniques for gene transfer, insertion, or conversion, and of embryo implantation procedures, the technical barriers to such an intervention seem easily surmountable. Unintended changes in DNA may occur when gametes are manipulated or stored.

In-utero gene transfer--an approach to the treatment of inherited lung diseases.

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Gene therapy in the treatment of disease

Gene therapy or transfer is increasingly used as a therapeutic modality in diseases that span the medical spectrum. The American Academy of Allergy and Immunology and the National Institute of Allergy and Infectious Diseases jointly sponsored the Symposium, "Gene Therapy in the Treatment of Disease," which was held December 6, 1993 at the National Institutes of Health (NIH). The program committee consisted of Lawrence Lichtenstein, MD, PhD, (Baltimore) Chairman; Philip Fireman, MD, (Pittsburgh); Howard B. Dickler, MD, (Bethesda); William Paul, MD, (Bethesda); and Raif Geha, MD, (Boston). Eight outstanding presentations on current and potential uses of gene therapy were provided by speakers who are leading researchers in this area of broad interest and unusually promising clinical application. This report summarizes the highlights of those presentations.