Safety of Genetically Engineered Foods Approaches to Assessing Unintended Health Effects (2004) / Chapter Skim
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Subreport: Methods and Mechanisms of Genetic Manipulation and Cloning of Animals
Subreport: Methods and Mechanisms of Genetic Manipulation and Cloning of Animals
Pages 217-236
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INTRODUCTION Since the onset of modern biotechnology, scientists have made discoveries leading to the development of new techniques for animal agriculture. Applications of biotechnology to animal agriculture include improving milk production and composition; increasing growth rate of meat animals; improving productive efficiency, or gain-to-feed ratios, and carcass composition; increasing disease resistance; enhancing reproductive performance; increasing prolificacy; and altering cell and tissue characteristics for biomedical research and manufacturing.
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Animals selected for cloning will be of great value because of their increased genetic merit for increased food production, disease resistance, and reproductive efficiency, or will be valued because they have been genetically modified to produce organs for transplantation or products with biomedical application. Before entering the marketplace, new agricultural biotechnologies are evaluated rigorously by the appropriate federal regulatory agencies to ensure efficacy, consumer safety, and animal health and well-being.
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Although clone is descriptive for multiple approaches for cloning animals, in this report clone is used as a descriptor for somatic cell nuclear transfer. Animal cloning during the late 1980s resulted from the transfer of nuclei from blastomeres of early cleavage-stage embryos into enucleated oocytes, and cloning of livestock and laboratory animals has resulted from transferring a nucleus from a somatic cell into an oocyte from which the nucleus has been removed (Westhusin et al., 2001; Wilmut et al., 1997)
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At the blastocyst stage, de novo methylation is lineage-specific as the inner cell mass, or embryonic disc, becomes highly methylated and trophectoderm becomes hypomethylated. These epigenetic reprogramming events appear to be deficient in cloned embryos that have abnormal patterns of DNA methylation and gene expression.
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Linker histone H1 and somatic cell histone H1 are important regulators of gene expression. Their expression changes from absent to very low during early embryonic development to low to moderate at the time of activation of the embryonic genome, and somatic cell histone H1 is lost from most mouse nuclei soon after transfer depending on cell cycle stage for donor and recipient cells.
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There is no evidence that the basic genome of cloned animals differs from that of the donor of cells used for somatic cell nuclear cloning. While most cloned animals do not survive, there is considerable evidence that a very low percentage of cloned embryos do survive because of inappropriate silencing or over-expression of genes due to abnormalities such as genome methylation, histone assembly into nucleosomes, or chromatin remodeling by linker histones, polycomb group proteins, nuclear scaffold proteins, and transcription factors.
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. EVALUATING METHODS TO DETECT POTENTIAL UNINTENDED COMPOSITIONAL CHANGES AND ADVERSE HEALTH EFFECTS OF FOODS DERIVED FROM CLONED ANIMALS Background Historically, equivalence of tissue or food composition has been an important component of the regulatory process to evaluate food safety (CAST, 2001; Falk et al., 2002; Juskevich and Guyer, 1990)
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The current regulatory view of FDA is that gene-based modification of animals for food production falls under the Center for Veterinary Medicine regulations as new "animal drugs." Since epigenetic changes in the genome may lead to changes in expression of one or more genes in a manner that may be analogous to gene expression changes observed in transgenic animals, the committee determined that cloned animals should initially be evaluated in a manner that is comparable to that for animals in which genetic engineering has been used to make specific genetic modifications. The committee also determined that cloned animals developed from transgenic parent stock for the purpose of producing pharmaceutical compounds, biomaterials, and other products not related to food production, not be allowed to enter the food chain.
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Evaluation of Unintended Composition Changes Various analytical methods can be utilized to identify compositional changes in food, irrespective of whether these are intended or unintended (Kuiper et al., 2003; also discussed in detail in Chapter 4 of the main report)
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For cloned animals, it will be important to establish a comparable list. Box 1a and 1b present proposed lists of nutrients that could be quantified as part of the compositional equivalence determination for cloned animals.
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Integration of Targeted and Nontargeted Approaches Integration of both targeted and nontargeted approaches is a promising means to assess whether cloning has induced unintended changes in composition of meat or milk. Figure 2 presents a flow chart illustrating sequential and parallel assay steps that could be part of the profiling approach for detecting unintended effects.
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. Regardless of the analytical approaches taken to establish compositional equivalence, the following two issues must be addressed.
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There is no scientific evidence that cloning is associated with any unintended compositional change that results in an unintended health consequence in humans. Since FDA treats genetic modification of animals as a new animal drug, it is beneficial to use the review process for recombinant bST as a case study to comment on methods of approach for evaluating health effects of foods derived from cloned animals.
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As previously discussed, however, the nontargeted profiling techniques are not yet appropriate to use as a reliable and reproducible means to assess unintended changes in mRNA, protein, or metabolite levels. The committee concluded it is important that research be supported to evolve and refine the nontargeted profiling methodologies that, as mentioned previously, include DNA microarray, proteomics, and metabolomics.
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. At present, there is no supportive evidence for increased risk to consumers of animal products from cloned animals, with the exception that it would not be prudent to allow animals that are genetically engineered to produce pharmaceuticals or other biologics, such as silk, to enter the food chain.
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However, should subsequent scientific review establish an increased risk to human health associated with the consumption of food products from cloned animals, it will be necessary to distinguish cloned animals from noncloned animals prior to entry into the food chain. It is envisioned that the greatest likelihood of increased risk may arise from cloned, transgenic animals in which the genetic modification, as the result of transgenesis, has been made for the production of biomaterials or pharmaceuticals.
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5. Animal identity and identity preservation systems should be improved for tracking animals and animal products through the food chain.
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2003. Epigenetic marking correlates with developmental potential in cloned bovine preimplantation embryos.
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2002. Somatic cell nuclear transfer.
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