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PubMed2004

Causation of nervous system tumors in children: insights from traditional and genetically engineered animal models.

Pediatric neurogenic tumors include primitive neuroectodermal tumors (PNETs), especially medulloblastoma; ependymomas and choroid plexus papillomas; astrocytomas; retinoblastoma; and sympathetic neuroblastoma. Meningiomas and nerve sheath tumors, although uncommon in childhood, are also significant because they can result from exposures of children to ionizing radiation. Specific chromosomal loci and specific genes are related to each of these tumor types. Virtually all these genes appear to act as tumor suppressor genes, which are inactivated in tumor cells by mutations or by chromosomal loss. In genetically engineered mice, some genes that are clearly associated with specific human tumors (e.g., RB1 in retinoblastoma and NF2 in meningiomas and schwannomas) have no such effect. Other genetic constructs in mice involving the genes p53, ptc1, and Nf1 have produced tumors remarkably similar to some of the human pediatric neoplasms. Some of these tumors become clinically apparent after only a few weeks, while the mice are still juveniles, especially when two or more tumor suppressor genes are inactivated in the same genetic construct. Conversely, at least one genetic pathway in rodents involving point mutation in the coding region of a transforming gene (neu in malignant schwannomas) does not appear to operate in any human tumors. The nervous system is markedly susceptible to experimental carcinogenesis during early life in rodents, dogs, primates, and other nonhuman species, and there is no obvious reason why this generalization should not also apply to humans. However, except for therapeutic ionizing radiation, no physical, chemical, or biological cause of human pediatric nervous system tumors is known. The failure of experimental transplacental carcinogenesis to mirror human pediatric experience more closely may reflect the need for multiple mutational events in target cells, and for experimental carcinogens that are capable of causing the full spectrum of mutations that occur in cancer-related genes in pediatric neurogenic tumors.

Adult↗
PubMed2000

Lessons from genetically engineered animal models VIII. Absorption and secretion of ions in the gastrointestinal tract.

Absorption and secretion of ions in gastrointestinal and other epithelial tissues require the concerted activities of ion pumps, channels, symporters, and exchangers, which operate in coupled systems to mediate transepithelial transport. Our understanding of the identities, membrane locations, and biochemical activities of epithelial ion transporters has advanced significantly in recent years, but major gaps and uncertainties remain in our understanding of their physiological functions. Increasingly, this problem is being addressed by the analysis of mutant mouse models developed by gene targeting. In this review, we discuss gene knockout studies of the secretory isoform of the Na(+)-K(+)-2Cl(-) cotransporter, isoforms 1, 2, and 3 of the Na(+)/H(+) exchanger, and the colonic H(+)-K(+)-ATPase. This approach is leading to a clearer understanding of the functions of these transporters in the living animal.

Animals↗
PubMed2002

Welfare issues of genetically modified animals.

Genetically engineered animals have opened new frontiers in the study of physiology and disease processes. Mutant animals offer more accurate disease models and increased precision for pathogenesis and treatment studies. Their use offers hope for improved therapy to patients with conditions that currently have poor or ineffective treatments. These advantages have fostered an increase in studies using mice in recent years, a development viewed with alarm by those who oppose the use of animals in research. Scientists point out that the mice are replacing more sentient species, such as nonhuman primates, and are increasing the quality of research being conducted. They assert that study of genetically engineered animals will eventually permit decreases in numbers of animals used in research. Nevertheless, the increase in use of genetically altered animals presents many challenges in reviewing protocols and providing care. Identification and resolution of any welfare problems is a responsibility that is shared by institutional animal care and use committee, veterinary, animal care, and research staffs. To identify potential welfare concerns, a database such as TBASE ( ) can be searched to learn what has been reported for established mutant lines. In addition, newly created lines should be monitored by a surveillance system and have phenotype assessment to identify the effects of altering the genome. Methods of ensuring welfare can include treatment of conditions produced, restriction of gene expression to tissues of interest or to certain time periods, and establishment of endpoints for removing animals from a study before problems appear.

Animal Husbandry↗
PubMed1999

Lessons from genetically engineered animal models. III. Lessons learned from gastrin gene deletion in mice.

Gastrin is the principal hormonal inducer of gastric acid secretion. Chronic hypergastrinemia, leading to hypersecretion of gastric acid and increased proliferation of parietal and enterochromaffin-like (ECL) cells, has been well described. In contrast, the physiological consequences of chronic gastrin deficiency had been poorly understood until the recent genetic engineering of mouse mutants containing a gastrin gene deletion by homologous recombination in embryonic stem cells. This themes article describes the consequences of constitutive gastrin deficiency on the development and physiology of the stomach. A lack of gastrin disrupts basal gastric acid secretion and renders the acid secretory system unresponsive to acute histaminergic, cholinergic, and gastrinergic stimulation. The defect in acid secretion is greater than would have been predicted from previous studies in which gastrin action was acutely blocked. Cellular changes include thinning of the gastric mucosa in the gastrin-deficient mice, with a reduction in parietal cells and reduced expression of markers of parietal and ECL cell-differentiated functions. The results suggest that gastrin is required for the functional maturation of the acid-secretory system.

Animals↗
PubMed2000

Commodifying animals: ethical issues in genetic engineering of animals.

The genetic modification of living beings raises special ethical concerns which go beyond general discussion of animal rights or welfare. Although the goals may be similar, biotechnology has accelerated the process of modification of types traditionally carried out by cross-breeding. These changes are discussed in relation to two areas: biomedicine, and animal husbandry. Alternative ethical approaches are reviewed, and it is argued that the teleological thesis underlying virtue ethics has special relevance here. The case for and the case against genetic engineering and patenting of life-forms are examined, and conclusions are drawn which favour regulation, caution and respect for animals and animal species.

Animal Experimentation↗
PubMed2000

Lessons from genetically engineered animal models XI. Novel mouse models to study pathogenic mechanisms of Crohn's disease.

Crohn's Disease (CD) affects more than 500,000 individuals in the United States and represents the second most common chronic inflammatory disorder after rheumatoid arthritis. Although major advances have been made in defining the basic mechanisms underlying chronic intestinal inflammation, the precise etiopathogenesis of CD remains unknown. We have recently characterized two novel mouse models of enteritis that express a CD-like phenotype, namely the TNF DeltaARE model of tumor necrosis factor (TNF) overexpression and the SAMP1/Yit model of spontaneous ileitis. The unique feature of these models is that they closely resemble CD for location and histopathology. These genetically manipulated new models of intestinal inflammation offer a powerful tool to investigate potential causes of human disease and may allow the development of novel disease-modifying therapeutic modalities for the treatment of CD.

Animals↗
PubMed2005

Pathophysiology of acute experimental pancreatitis: lessons from genetically engineered animal models and new molecular approaches.

The incidence of acute pancreatitis is growing and worldwide population-based studies report a doubling or tripling since the 1970s. 25% of acute pancreatitis are severe and associated with histological changes of necrotizing pancreatitis. There is still no specific medical treatment for acute pancreatitis. The average mortality resides around 10%. In order to develop new specific medical treatment strategies for acute pancreatitis, a better understanding of the pathophysiology during the onset of acute pancreatitis is necessary. Since it is difficult to study the early acinar events in human pancreatitis, several animal models of acute pancreatitis have been developed. By this, it is hoped that clues into human pathophysiology become possible. In the last decade, while employing molecular biology techniques, a major progress has been made. The genome of the mouse was recently sequenced. Various strategies are possible to prove a causal effect of a single gene or protein, using either gain-of-function (i.e., overexpression of the protein of interest) or loss-of-function studies (i.e., genetic deletion of the gene of interest). The availability of transgenic mouse models and gene deletion studies has clearly increased our knowledge about the pathophysiology of acute pancreatitis and enables us to study and confirm in vitro findings in animal models. In addition, transgenic models with specific genetic deletion or overexpression of genes help in understanding the role of one specific protein in a cascade of inflammatory processes such as pancreatitis where different proteins interact and co-react. This review summarizes the recent progress in this field.

Animals↗
PubMed1999

Lessons From Genetically Engineered Animal Models VI. Liver repopulation systems and study of pathophysiological mechanisms in animals.

The ability to localize transplanted hepatocytes in the liver offers exciting new opportunities. Transplanted hepatocytes enter liver plates, form hybrid plasma membrane structures with adjacent hepatocytes, express liver genes correctly, and survive indefinitely. The transplanted cell mass is regulated, such that cell proliferation is limited in the normal adult liver, whereas the liver is repopulated extensively when proliferation rates in transplanted and host hepatocytes become dissociated or host hepatocytes are ablated selectively. Transplanted hepatocytes are susceptible to hepatitis viruses. These aspects of transplanted hepatocyte biology indicate that liver repopulation systems can help address questions concerning pathophysiological mechanisms.

Animals↗
PubMed1996

Genetically Engineered Animal Models of Alzheimer's Disease

The application of transgenic research has proven to be a powerful and popular tool for investigating the contribution of specific genes known or suspected to be involved in the pathology of Alzheimer's disease. Many different experimental approaches have been pursued in an effort to mimic one or more of the numerous and diverse features characterizing Alzheimer's disease. Results have been variable but not without successes. Some of the cardinal hallmarks of this disorder have been recapitulated through the manipulation of a single gene, providing information on the interrelationship between several pathological events. Also, through the generation of such transgenic animals, potential models are being established for this disease that will be valuable for development of intervention strategies.

Journal Article↗
PubMed1999

Lessons from genetically engineered animal models. V. Knocking out genes to study liver regeneration: present and future.

Studies utilizing knockout mice have contributed important new knowledge about the mechanisms that initiate liver regeneration. New mouse lines need to be established to address major questions about these mechanisms, targeting genes for which there is experimental evidence of their involvement in important pathways. Development of conditional, liver-specific knockout mice would be of great value for these studies.

Animals↗
PubMed2000

Lessons from genetically engineered animal models. VII. Apoptosis in intestinal epithelium: lessons from transgenic and knockout mice.

Apoptosis plays an important role in homeostasis of intestinal epithelia and is also a stress response to toxic stimuli. Transgenic and knockout mice have provided insights into the regulation of intestinal epithelial apoptosis that could not have been obtained by cell culture techniques. Two broad types of apoptosis have been characterized: spontaneous apoptosis, which occurs continuously at low levels in the normal, unstressed intestine, and stress-induced apoptosis, which occurs after genotoxic insult such as exposure to gamma radiation or DNA-damaging drugs. Spontaneous apoptosis occurs at the base of the crypt at or near the position of epithelial stem cells. Knockout studies have shown that spontaneous apoptosis is independent of p53 and Bax in both small and large intestine, whereas Bcl2 only regulates spontaneous apoptosis in the colon. Little is known about the regulation of the specialized form of cell death at the villus tip. In contrast, knockout studies have demonstrated that both p53 and Bcl2 are important regulators of stress-induced apoptosis but that there are significant differences between early and late time points. Bax plays only a minor role in the regulation of stress-induced apoptosis. The cumulative effect of stress-induced apoptosis on tissue architecture is not straightforward, and cell cycle arrest also plays a critical role. Nevertheless, p53 is an important determinant of the histopathological damage induced by 5-fluorouracil in murine intestinal epithelium. These studies have important implications for the development of more effective treatment for inflammatory bowel disease and cancer.

Animals↗
PubMed1996

Bad ethics, good ethics and the genetic engineering of animals in agriculture.

Genetic engineers have been remiss in addressing ethical and social issues emerging from this powerful new technology, a technology whose, implications for agriculture are profound. As a consequence of this failure, society has been uneasy about genetic engineering of animals and has had difficulty distinguishing between genuine and spurious ethical issues the technology occasions. Many of the most prominent concerns do not require a serious response. On the other hand, concerns about a variety of possible risks arising from genetic engineering of animals require careful consideration and dialogue with the public. Such concerns are an admixture of ethics and prudence. A purely ethical challenge, however, hitherto not addressed, is represented by problems of animal welfare that arise out of genetically engineering agricultural animals. A principle of "conservation of welfare" is suggested as a plausible moral rule to guide such genetic engineering.

Animal Experimentation↗
PubMed1993

Patents for genetically modified animals.

Should genetically engineered animals be patented? This issue has been one of the most contentious as lawmakers have grappled with how best to protect intellectual property. Since the 1980 case of Diamond v. Chakrabarty, in which the U.S. Supreme Court ruled that a living microorganism is patentable, the U.S. Patent and Trademark Office has determined that plants and nonhuman animals can be patented. These policy decisions have led to congressional debate on whether animals should be patentable subject matter. Patenting of living organisms is unique for three reasons: the invention itself is alive; the invention in some instances can reproduce itself; and the invention sometimes cannot be adequately described for patent specification purposes, leading to the need for deposit of the invention for patent purposes.

Animals↗