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PubMed1994

Genetically engineered in vitro systems for biotransformation studies.

In order to understand cytochrome P450-mediated metabolism of xenobiotics such as drugs and pollutants, several cell systems are genetically engineered for metabolic competence by cloning cDNAs encoding cytochrome P450 and other enzymes and by heterologous expression in bacterial, yeast, and mammalian cells. Genetically engineered cell systems are defined for the cDNA enzyme function. In conjunction with cell intrinsic properties, these genetically engineered cell systems can be used for the assessment of metabolism-dependent pharmacological and/or toxicological effects.

Animals↗
PubMed2006

Encapsulation cell therapy for mucopolysaccharidosis type VII using genetically engineered immortalized human amniotic epithelial cells.

Mucopolysaccharidosis type VII (MPSVII) is a lysosomal storage disease resulted from a deficiency of the enzyme beta-glucuronidase (GUSB), which is necessary for degradation of glycosaminoglycans (GAGs). The deficiency of GUSB causes progressive accumulation of GAGs and subsequent lysosomal distension in multiple tissues, including the central nervous system (CNS). In murine experiments, bone marrow transplant, enzyme replacement, viral vectors, and genetically modified cells were successfully used for correction of the visceral accumulation of GAGs, but little improvement was seen in the brain, because these therapeutic agents cannot cross the blood-brain barrier (BBB). Although direct intracerebral injection of GUSB-encoding viral vectors has been developed to bypass the BBB, the possibility of tumor formation and the toxicity of over-expressed GUSB have been reported. In this study, we generated immortalized human amniotic epithelial (IHAE) cells to maintain the effect of implantation, and encapsulated these cells to prevent harmful immunological response and tumor formation and to regulate the level of GUSB expression within the host. Moreover, we generated IHAE cells that over-express and secrete human GUSB following transduction with an adenoviral vector encoding human GUSB. Therapeutic efficacy for MPSVII was evaluated in and ex vivo experiments using these encapsulated genetically engineered GUSB-encoding IHAE cells. We confirmed that encapsulated genetically engineered IHAE cells could secrete significant amounts of GUSB outside the capsule in vitro and into the cerebral parenchyma of C3H mice seven days after the capsule implantation. Thus, encapsulation cell therapy using genetically engineered IHAE cells is an effective armamentarium for the treatment of MPSVII.

Amnion↗
PubMed2005

A comparative risk assessment of genetically engineered, mutagenic, and conventional wheat production systems.

Wheat (Triticum aestivum L.) varieties produced using modern biotechnologies, such as genetic engineering and mutagenic techniques, have lagged behind other crop species, but are now being developed and, in the case of mutagenic wheat, commercially grown around the world. Because these wheat varieties have emerged recently, there is a unique opportunity to assess comparatively the potential environmental risks (human health, ecological, and livestock risks) associated with genetically engineered, mutagenic, and conventional wheat production systems. Replacement of traditional herbicides with glyphosate in a glyphosate-tolerant (genetically engineered) wheat system or imazamox in an imidazolinone-tolerant (mutagenic) wheat system may alter environmental risks associated with weed management. Additionally, because both systems rely on plants that express novel proteins, the proteins and plants themselves may impose risks. The purpose of our study was to examine comparatively the multiple aspects of risk associated with different wheat production systems in the US and Canada using the risk assessment paradigm. Specifically, we used tier 1 quantitative and qualitative risk assessment methods to compare specific environmental risks associated with the different wheat production systems. Both glyphosate and imazamox present lower human health and ecological risks than many other herbicides associated with conventional wheat production systems evaluated in this study. The differences in risks were most pronounced when comparing glyphosate and imazamox to herbicides currently with substantial market share. Current weight-of-evidence suggests that the transgenic CP4 EPSPS protein present in glyphosate-tolerant wheat poses negligible risk to humans, livestock, and wildlife. Risk for mutated AHAS protein in imidazolinone-tolerant wheat most likely would be low, but there are not sufficient effect and exposure data to adequately characterize risk. Environmental risks for herbicides were more amenable to quantitative assessments than for the transgenic CP4 EPSPS protein and the mutated AHAS protein.

3-Phosphoshikimate 1-Carboxyvinyltransferase↗
PubMed1998

Noninvasive In vivo high-resolution magnetic resonance imaging of atherosclerotic lesions in genetically engineered mice.

BACKGROUND: The pathogenesis of atherosclerosis is currently being investigated in genetically engineered small animals. Methods to follow the time course of the developing pathology and/or the responses to therapy in vivo are limited. METHODS AND RESULTS: To address this problem, we developed a noninvasive MR microscopy technique to study in vivo atherosclerotic lesions (without a priori knowledge of the lesion location or lesion type) in live apolipoprotein E knockout (apoE-KO) mice. The spatial resolution was 0.0012 to 0.005 mm3. The lumen and wall of the abdominal aorta and iliac arteries were identified on all images in apoE-KO (n=8) and wild-type (n=5) mice on chow diet. Images obtained with MR were compared with corresponding cross-sectional histopathology (n=58). MR accurately determined wall area in comparison to histopathology (slope=1.0, r=0.86). In addition, atherosclerotic lesions were characterized in terms of lesion shape and type. Lesion type was graded by MR according to morphological appearance/severity and by histopathology according to the AHA classification. There was excellent agreement between MR and histopathology in grading of lesion shape and type (slope=0.97, r=0.91 for lesion shape; slope=0. 64, r=0.90 for lesion type). CONCLUSIONS: The combination of high-resolution MR microscopy and genetically engineered animals is a powerful tool to investigate serially and noninvasively the progression and regression of atherosclerotic lesions in an intact animal model and should greatly enhance basic studies of atherosclerotic disease.

Animals↗
PubMedDate not supplied

Functional dynamics of living systems and genetic engineering.

The discussion on Genetically Modified Organisms (GMO's) has been centred mainly on the nature and effects on economy, human health, environment, of the few transgenic plant lines present in the market in the last eight years. On the contrary, the present paper starts with a discussion of some of the relevant changes in our basic knowledge of the structure and dynamics of living systems in the last twenty years. Contemporary Biology is then compared with what may be called the "modern paradigm" of life sciences on which present day GMO's are conceptually based. Technical, environmental, social and economic problems deriving from the unexpected, persistent prevalence of the old fashioned modern vision of life in the "spirit of time" will be thoroughly discussed with a particular attention to the virtualisation process of GMO's and the effects of the prevalence over economic, social, environmental reality of their symbolic values.

Animals↗
PubMed1999

Interpretation of phenotype in genetically engineered mice.

BACKGROUND AND PURPOSE: In mice, genetic engineering involves two general approaches-addition of an exogenous gene, resulting in transgenic mice, and use of knockout mice, which have a targeted mutation of an endogenous gene. The advantages of these approaches is that questions can be asked about the function of a particular gene in a living mammalian organism, taking into account interactions among cells, tissues, and organs under normal, disease, injury, and stress situations. METHODS: Review of the literature concentrating principally on knockout mice and questions of unexpected phenotypes, lack of phenotype, redundancy, and effect of genetic background on phenotype will be discussed. CONCLUSION: There is little gene redundancy in mammals; knockout phenotypes exist even if none are immediately apparent; and investigating phenotypes in colonies of mixed genetic background may reveal not only more phenotypes, but also may lead to better understanding of the molecular or cellular mechanism underlying the phenotype and to discovery of modifier gene(s).

Animals↗
PubMed1992

The effect of genetically engineered glucagon on glucose recovery after hypoglycaemia in man.

To compare the effect on glucose recovery after insulin-induced hypoglycaemia of intramuscular genetically engineered glucagon, intramuscular glucagon from pancreatic extraction and intravenous glucose, we examined 10 healthy subjects during blockage of glucose counterregulation with somatostatin, propranolol and phentolamine. Each subject was studied on three separate occasions. Thirty min after a bolus injection of 0.075 iu soluble insulin per kilogram body weight the subjects received one of the following treatments: 1 mg glucagon from pancreatic extraction intramuscularly; 1 mg genetically engineered glucagon intramuscularly; and 25 g glucose intravenously, respectively. The two glucagon preparations induced an equally rapid increase in plasma glucose. This was due to an abrupt (within 4 min) and equal increase in glucose appearance rate. The increases in both plasma glucose and in glucose appearance rate were far more protracted after i.m. glucagon than after i.v. glucose. These results suggest that genetically engineered glucagon and glucagon from pancreatic extraction have a similar effect on hepatic glucose production rate. Due to the protracted effect of intramuscular glucagon, a combined treatment consisting of both intravenous glucose and intramuscular glucagon may be more effective in the treatment of hypoglycaemia than any of these given alone.

Adult↗
PubMed2005

Conceptualizing "suicidal genetically engineered microorganisms" for bioremediation applications.

Use of genetically modified microorganisms (GEMs) for pollution abatement has been limited because of risks associated with their release in the environment. Recent developments in the area of recombinant DNA technologies have paved the way for conceptualizing "suicidal genetically engineered microorganisms" (S-GEMS) to minimize such anticipated hazards and to achieve efficient and safer bioremediation of contaminated sites. Our strategy of designing a novel S-GEM is based on the knowledge of killer-anti-killer gene(s) that would be susceptible to programmed cell death after detoxification of any given contaminated site(s).

Bacteria↗
PubMed1997

Genetically engineered mice as animal models for NIDDM.

Genetically engineered animals carrying defined alterations in their genome can represent invaluable tools for better understanding complex polygenic diseases such as non-insulin-dependent diabetes mellitus (NIDDM) at the molecular level. The structure or expression of a number of genes potentially involved in insulin action or pancreatic beta-cell function have recently been altered in the mouse using transgenic or gene-targeting approaches. The obtention of such mice is the first step towards the development of animal models carrying multiple gene defects which would be very useful in NIDDM research.

Animals↗
PubMed1988

New approaches to animal vaccines utilizing genetic engineering.

Control of infectious diseases in livestock is an important determinant in the success of a nation's effort to efficiently meet its need for animal products. Genetic engineering offers many new options in the design of animal vaccines. Monoclonal antibodies, DNA cloning, recombination, and transfection are examples of techniques that facilitate innovative strategies in antigen identification, production, and delivery. This article reviews the use of genetic engineering in the production of vaccines directed against foot-and-mouth disease virus and other important pathogens of animals. The advantages and disadvantages of vaccines produced through the use of genetic engineering are discussed.

Animal Diseases↗
PubMed2006

[Preparation of new protein carrier of vaccine against pneumococcal otitis media with genetic engineering technology].

OBJECTIVE: To prepare pneumolysin as a new protein carrier of vaccine against otitis media with genetic engineering technology and establish the base of the study on pneumococcal conjugative vaccines. METHODS: Genomic DNA was isolated from streptococcus pneumoniae. A pair of primers which included two restriction sites was designed based on the published pneumolysin gene sequence. The pneumolysin gene was amplified from pneumococcal DNA with PCR technology. The restriction enzyme digested fragment was linked into the cloning vector PET-28a and the recombinant plasmid DNA containing pneumolysin was then transfected into host cell E. coli JM109 (DE3). RESULTS: DNA fragments were subcloned to construct the complete pneumolysin gene by a conventional coning and PCR. The inserted pneumolysin gene sequence was confirmed by DNA sequencing and the pneumolysin protein was successfully expressed. The relative molecular mass of the expressed product was 52 000. The expressed product amounted to 8% of the total host cell protein. CONCLUSIONS: The pneumolysin gene was successfully cloned into host cell using genetic engineering technology. The recombinant pneumolysin was expressed and purified for preparation. This work laid a foundation of the preparation of pneumococcal conjugative vaccines.

Bacterial Proteins↗
PubMed1994

Efficient fuzzy control strategies for the application of pH-stat to fed-batch cultivation of genetically engineered Escherichia coli.

In the cultivation of genetically engineered Escherichia coli it is very important to control the substrate concentration at an appropriate level in order to avoid the accumulation of acetate, thereby elevating the expression level of plasmid-encoded protein. In this paper, a pH-stat mode of fuzzy control was considered for the overexpression of beta-galactosidase in the fed-batch cultivation of recombinant E. coli. In the simple pH-stat fuzzy control, the response of pH change in the culture broth to the feeding rate of glucose was used to estimate the glucose consumption rate. In the modified pH-stat fuzzy control, the glucose consumption rate was accurately estimated by using pH change and the change in the carbon dioxide content of the exhaust gas. With this control strategy, the cell density could be increased to 72 g DCW dm-3, which was twofold higher than that attained in the cultivation with the simple pH-stat fuzzy control. The bulk beta-galactosidase concentration was increased to 4150 U cm-3, which was threefold higher than when the simple pH-stat control was used.

Carbon Dioxide↗
PubMed1990

Solution hybridization assay for detecting genetically engineered microorganisms in environmental samples.

A solution hybridization method was developed for detecting genetically engineered microorganisms in environmental samples. The detection method involves recovery of DNA from the microbial community of an environmental sample followed by hybridization in solution with a radiolabeled RNA gene probe. After nuclease digestion of non-hybridized probe RNA, the DNA-RNA hybrids formed in the solution hybridization reaction are separated by sephadex or hydroxyapatite column chromatography and detected by liquid scintillation counting. Using solution hybridization-gene probe detection, as few as 100-1000 target cells per gram sediment sample of a 2,4,5-T-degrading genetically engineered microorganisms could be detected.

Chromatography, Gel↗
PubMed1990

Detection of genetically engineered traits among bacteria in the environment.

The release of genetically engineered microorganisms (GEMs) into the environment has, as its main aims, the benefits of improved agricultural yield and control of environmental pollution. However, effective and safe release programmes necessitate the development of sensitive, selective detection methods to monitor the environmental impact of released organisms.

Bacteria↗
PubMed1991

[Genetic engineering].

This paper deals with the progress made in genetic engineering techniques, capable of altering the genetic potential of an organism, either by the introduction or the suppression of new structural genes. Some of the general applications are described as are also, more particularly, their uses in the field of medicine. A critical analysis of the benefits and risks involved is also undertaken.

Antibodies, Monoclonal↗
PubMed1988

Aerial Dispersal and Epiphytic Survival of Pseudomonas syringae during a Pretest for the Release of Genetically Engineered Strains into the Environment.

Prospective experimental field evaluation of genetically engineered microorganisms, such as microbial pest control agents, raises issues of how to properly ascertain their fate and survival in the environment. Field trials with recombinant organisms must reflect requirements for sampling and monitoring. Field trials were conducted at Tulelake, Calif., to monitor the numbers of viable cells of a nonrecombinant strain of Pseudomonas syringae that entered the atmosphere and landed on plants and soil during and after an aerosol spray application. An exponential decrease in numbers of viable cells deposited at increasing distances from three sprayed plots was observed. The relative rate of survival of cells sprayed directly on plants was more than 10 times higher than that of cells dispersed through the air to similar adjacent plants. Results are being used to gain experience with the characteristics of a release site that influence containment or dispersal and to develop appropriate sampling methodologies for evaluating survival and dispersal characteristics of genetically engineered bacteria released into the environment. The ability to make predictions about microbial dispersal and survival will reduce the uncertainties associated with environmental releases of recombinant organisms.

Journal Article↗
PubMed2005

In vivo cervical cancer growth inhibition by genetically engineered cytotoxic T cells.

PURPOSE: The CD44 v7/8 splice variant that is frequently expressed in cervical carcinoma and rarely expressed in normal tissues displays promising properties as a target antigen for cancer immune therapy. In this study, cytotoxic T lymphocytes (CTLs) were genetically engineered to gain CD44v7/8 target specificity. METHODS: Clone 96 (Cl96), an established murine cytotoxic T-cell line, and naïve murine T cells were retrovirally transduced with a fusion gene construct encoding for the single chain fragment scFv of the monoclonal antibody VFF17 and for the zeta chain of the T-cell receptor (TCR). The therapeutic potential of genetically engineered T cells was tested in vitro and in vivo. RESULTS: Surface expression of the chimeric TCR on infected Cl96 and naïve T cells was shown by FACS analysis. CD44v7/8-positive target cells were efficiently lysed by transduced Cl96 and naïve T cells, demonstrating the functionality and specificity of the chimeric TCR. In a xenograft BALB/c mouse model, efficient growth retardation of CD44v7/8-positive tumours was mediated by genetically engineered Cl96(VFF17)cyYZ cells. CONCLUSIONS: We were able to reprogramme the target specificity of recombinant Cl96 and naïve CTLs resulting in efficient cytolysis of CD44v7/8-positive cervical cancer cells. High transduction rates and the specific cytolysis of CD44v7/8-redirected CTLs are promising tools for an immune gene therapy approach for advanced cervical cancer.

Animals↗