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PubMed2002

Delayed rejection of porcine cartilage is averted by transgenic expression of alpha1,2-fucosyltransferase.

The use of xenogeneic cells or tissues for tissue engineering applications may lead to advances in biomedical research. Hyperacute and delayed rejection are immunologic hurdles that must be addressed to achieve xenograft survival in the pig-to-primate setting. Expression of human alpha1,2-fucosyltransferase (HT) in the donor cell or tissue protects from hyperacute rejection (HAR) by reducing expression of Galalpha1,3-Gal epitope, the major xenoantigen recognized by human natural antibodies. We hypothesized that Galalpha1,3-Gal antigen contributes to delayed tissue rejection. To test this hypothesis, we transplanted control or HT-transgenic engineered porcine cartilage s.c. into alpha1,3-galactosyltransferase knockout (Gal KO) mice. Control porcine cartilage grafted in Gal KO mice was not susceptible to HAR but was rejected in several wk by a prominent cellular immune infiltrate and elevated antibody titers. In contrast, Gal KO mice receiving the HT engineered cartilage showed a markedly reduced anti-pig antibody response and no anti-Galalpha1,3-Gal-elicited antibody response. The HT implants had a mild cellular infiltrate that was confined to the graft periphery. Our study demonstrates that a marked reduction of Galalpha1,3-Gal antigen in HT-transgenic porcine cartilage confers resistance to a process of delayed rejection. Further development of tissue engineering applications that use genetically modified porcine tissues is encouraged.

Animals↗
PubMed2000

Public concern about genetics.

Throughout the twentieth century and continuing into the present, the general public has been fascinated by advances in genetic knowledge. At times, individuals and groups have either inadvertently or deliberately misused genetic knowledge in the service of political goals. At other times, advances in genetics have challenged deeply held societal or religious beliefs. During the 1990s, there were many advances that focused an unprecedented level of public attention and concern on genetics. In particular, the public has expressed deep concern about gene mapping, cloning, and genetically modified foods. In each case, the origin of the concern and the nature of the public response have been different. I consider these topics and argue that the scientific community must increase its commitment to public discourse.

Animals↗
PubMedDate not supplied

In vivo and in vitro degradation of urea and uric acid by encapsulated genetically modified microorganisms.

This study was undertaken to characterize the capacity of a combination of genetically modified bacteria to lower elevated levels of urea and uric acid and thus to serve as a potential adjunct to maintenance dialysis in patients with chronic renal failure. Two strains of genetically modified bacteria expressing enzymes, urease to degrade urea and uricase to degrade uric acid, were identified, combined, and dispersed in 600-microm alginate microcapsules suitable for oral administration. In 24 h in vitro experiments, 5 mL of these capsules completely cleared 95% of the urea and >99% of the uric acid from 100 mL of a challenge solution formulated to the concentration of these solutes in a presenting hemodialysis patient. The process of urea degradation was found to be intracellular and each bacterial strain was specific for its substrate. Solute degradation in vivo was evaluated with a chemically induced model of acute renal failure, using Sprague-Dawley rats. Orally administered capsules were found to remain in the gastrointestinal tract for at least 6 h. The severity of azotemia and hyperuricaemia after chemical induction of acute renal failure was reduced by 64 and 31%, respectively, on administration of the capsules. Reduction of urea concentration (but not uric acid concentration) in vivo required coadministration of an ion-exchange resin to adsorb ammonia. Oral delivery of a combination of genetically modified microorganisms should be further explored in chronic renal failure models as a useful adjunct to dialysis or to immunosorption for the treatment of uremia.

Acute Kidney Injury↗
PubMed2005

Recent development in the field of international liability regimes to tackle environmental risks.

The polluter-pays principle requires States to take any actions that may be necessary to ensure that polluters bear the full environmental and social costs of their activities. One step to implement this principle is the development of regulations on environmental Civil Liability. The adoption of the UN-ECE Protocol on Civil Liability and Compensation for Damage caused by the Transboundary Effects of Industrial Accidents on Transboundary Waters (Kiev Protocol) in May 2003 was the result of a three-year negotiation process undertaken in the aftermath of the Baia Mare accident in Romania. The accident caused transboundary water pollution in the downstream countries Hungary and Yugoslavia. Owing to the absence of applicable liability rules, no compensation was ever paid for the damage caused by the pollution. The Cartagena Protocol on Biosafety mandates the Parties to establish rules and procedures in the field of liability and redress. Here there is likely to be a longer negotiation process before an agreed regime on liability and redress for damage arising from the use of living modified organisms (LMOs) becomes available, owing to the complexity and the particularities of gene technology.

Accidents, Occupational↗
PubMed2000

Attitudes of the public and scientists to biotechnology in Japan at the start of 2000.

This survey on biotechnology and bioethics was carried out on national random samples of the public and scientists in November 2000-January 2000 [sic]throughout Japan, and attendees at the Novartis Life Science Forum held on 29 September 1999 in Tokyo. The sample size was 297, 370, and 74 respectively. While there is a better awareness of GMOs in 2000 compared to 1991; the trend shows an increase in the perceived risks of GMOs followed by growing resistance in Japan. While a majority of persons believed genetic engineering would make life better over the next twenty years (57%), the proportion of respondents who thought genetic engineering would make life worse over the next twenty years doubled from 1997 to 2000 (from 12% to 25%). Respondents were asked whether they had heard about applications in several areas and the order of familiarity (high-low) was: pest-resistant crops, human genes in bacteria, mouse to develop cancer, food and drinks, pigs with human hearts and pre-implantation diagnosis. A divide of opinion can be seen when the results on benefit, risk and moral acceptability of applications of biotechnology by the public are compared to the forum and scientist samples. A significant change in the acceptance of the public occurred in 2000 where only 22% agreed on the moral acceptability of GM food compared to 41% in 1997. In 2000 fewer people said they are willing (20%) to buy genetically modified fruits that taste better compared to 1997 (36%). The results show less public support for use of gene therapy than 1993 and twice as many scientists rejected gene therapy than they did in 1991. When asked who is best placed to regulate modern biotechnology, the respondents were overwhelmingly in favor of international regulatory bodies, such as the United Nations and the World Health Organization (72%), rather than national bodies. The comparison between scientists and public is interesting, however the more enthusiastic sample were participants from the Novaritis Life Science Forum with its mixed occupations.

Biotechnology↗
PubMed2002

First synthesize new viruses then regulate their release? The case of the wild rabbit.

European wild rabbits originated in southwestern Europe but have been introduced into many other countries world-wide, becoming serious pests in many instances. As a consequence of rabbits being regarded so differently, applied research for their management often has opposing goals, namely their conservation or their control. Furthermore, modern gene technology has led to the concept of using genetically modified myxoma viruses for rabbit management, again with quite contrary aims in mind. In this paper we explain the possible ecological and economic consequences of using these genetically modified viruses inappropriately and we consider whether national and international regulations are sufficient to prevent improper use. If international regulations are inadequate, molecular biologists and ecologists must consider the consequences of their research and advice beyond their own country to avoid unwanted impacts.

Animals↗
PubMed2006

Immunogenicity of a malaria parasite antigen displayed by Lactococcus lactis in oral immunisations.

A putative protective protein from Plasmodium falciparum merozoites, MSA2, was expressed in two different ways on the cell surface of the Gram-positive food-grade bacterium, Lactococcus lactis. The first display format exploits an LPXTG-type anchoring motif of the lactococcal proteinase PrtP to covalently anchor MSA2 to the genetically modified producer cells. In a second display format, MSA2 was fused to the peptidoglycan-binding domain (Protein Anchor) of the lactococcal cell wall hydrolase AcmA and was non-covalently rebound to the surface of non-genetically modified, non-living high-binder L. lactis cells, termed Gram-positive enhancer matrix (GEM) particles. The L. lactis recombinants carrying covalently bound MSA2 were used to immunise rabbits through nasal and oral routes. The highest levels of IgG antibodies reacting with near-native MSA2 on merozoites was elicited by oral administration. Intestinal antibodies to MSA2 were produced only after oral immunisation. MSA2-specific T(h)-cell activation could be demonstrated. Based on these results, the immunogenicity in oral immunisations of MSA2, bound non-covalently to non-genetically modified L. lactis GEM particles, was compared with MSA2 that was bound covalently to genetically modified L. lactis. These two forms elicited similar titres of serum antibodies. The results illustrate the potential of using non-genetically modified L. lactis as a safe vaccine delivery vehicle to elicit systemic antibodies, thereby avoiding the dissemination of recombinant DNA into the environment.

Administration, Intranasal↗
PubMed2002

Effects of Pseudomonas putida modified to produce phenazine-1-carboxylic acid and 2,4-diacetylphloroglucinol on the microflora of field grown wheat.

Pseudomonas putida WCS358r, genetically modified to have improved activity against soil-borne pathogens, was released into the rhizosphere of wheat. Two genetically modified derivatives carried the phz or the phl biosynthetic gene loci and constitutively produced either the antifungal compound phenazine-1-carboxylic acid (PCA) or the antifungal and antibacterial compound 2,4-diacetylphloroglucinol (DAPG). In 1997 and 1998, effects of single introductions of PCA producing derivatives on the indigenous microflora were studied. A transient shift in the composition of the total fungal microflora, determined by amplified ribosomal DNA restiction analysis (ARDRA), was detected. Starting in 1999, effects of repeated introduction of genetically modified microorganisms (GMMs) were studied. Wheat seeds coated with the PCA producer, the DAPG producer, a mixture of the PCA and DAPG producers, or WCS358r, were sown and the densities, composition and activities of the rhizosphere microbial populations were measured. All introduced strains decreased from 10(7) CFU per gram of rhizosphere sample to below the detection limit after harvest of the wheat plants. The phz genes were stably maintained in the PCA producers, and PCA was detected in rhizosphere extracts of plants treated with this strain or with the mixture of the PCA and DAPG producers. The phl genes were also stably maintained in the DAPG producing derivative of WCS358r. Effects of the genetically modified bacteria on the rhizosphere fungi and bacteria were analyzed by using amplified ribosomal DNA restriction analysis. Introduction of the genetically modified bacterial strains caused a transient change in the composition of the rhizosphere microflora. However, introduction of the GMMs did not affect the several soil microbial activities that were investigated in this study.

Anti-Bacterial Agents↗
PubMed2004

Methods for the differential integrative omic analysis of plasma from a transgenic disease animal model.

Multitiered quantitative analysis of biological systems is rapidly becoming the desired approach to study hierarchical functional interactions between proteins and metabolites. We describe here a novel systematic approach to analyze organisms with complex metabolic regulatory networks. By using precise analytical methods to measure biochemical constituents and their relative abundance in whole plasma of transgenic ApoE*3-Leiden mice and an isogenic wild-type control group, simultaneous snapshots of metabolic and protein states were obtained. Novel data processing and multivariate analysis tools such as Impurity Resolution Software (IMPRESS) and Windows-based linear fit program (WINLIN) were used to compare protein and metabolic profiles in parallel. Canonical correlations of the resulting data show quantitative relationships between heterogeneous components in the TG animals. These results, obtained solely from whole plasma analysis allowed us, in a rapid manner, to corroborate previous findings as well as find new events pertaining to dominant and peripheral events in lipoprotein metabolism of a genetically modified mammalian organism in relation to ApoE3, a key mediator of lipoprotein metabolism.

Animals↗
PubMed2004

Therapy of experimental pseudomonas infections with a nonreplicating genetically modified phage.

Bacteriophage therapy of bacterial infections has received renewed attention owing to the increasing prevalence of antibiotic-resistant pathogens. A side effect of many antibiotics as well as of phage therapy with lytic phage is the release of cell wall components, e.g., endotoxins of gram-negative bacteria, which mediate the general pathological aspects of septicemia. Here we explored an alternative strategy by using genetically engineered nonreplicating, nonlytic phage to combat an experimental Pseudomonas aeruginosa infection. An export protein gene of the P. aeruginosa filamentous phage Pf3 was replaced with a restriction endonuclease gene. This rendered the Pf3 variant (Pf3R) nonreplicative and concomitantly prevented the release of the therapeutic agent from the target cell. The Pf3R phage efficiently killed a wild-type host in vitro, while endotoxin release was kept to a minimum. Treatment of P. aeruginosa infections of mice with Pf3R or with a replicating lytic phage resulted in comparable survival rates upon challenge with a minimal lethal dose of 3. However, the survival rate after phage therapy with Pf3R was significantly higher than that with the lytic phage upon challenge with a minimal lethal dose of 5. This higher survival rate correlated with a reduced inflammatory response elicited by Pf3R treatment relative to that with the lytic phage. Therefore, this study suggests that the increased survival rate of Pf3R-treated mice could result from reduced endotoxin release. Thus, the use of a nonreplicating modified phage for the delivery of genes encoding proteins toxic to bacterial pathogens may open up a new avenue in antimicrobial therapy.

Animals↗
PubMed2006

[Core-binding factor alpha1 gene modified marrow mesenchymal stem cells for repairing radial defects].

OBJECTIVE: To study the feasibility of core-binding factor alpha1 (Cbfal) gene modified marrow mesenchymal stem cells (MSCs) composed with porcine acellular bone extracellular matrix in repairing the radial defects. METHODS: Radial defects of 1.2 cm in length were created in 40 Japanese white rabbits and they were divided into four groups. In group A, MSCs isolated from homogeneous rabbits were infected with Cbfal recombinant adenovirus and implanted into acellular bone extracellular matrix, and then the complexes were implanted into defects. In group B, the complexes including the MSCs without Cbfal gene-modified and scaffold material were implanted into defects. In group C, only the scaffold material was implanted. In group D, defects were not treated as the control. The macroscopic, X-ray and histologic analysis were performed to evaluate the repair effect at 4, 8 and 12 weeks postoperatively. The repaired radius were examined by biomechanical test at 12 weeks postoperatively. RESULTS: By gross examination,mature hard new bone formed at grafted areas at 12 weeks postoperatively in group A, osteotomized ends connected by much callus in group B and less callus in group C at grafted areas. In contrast, bone nonunion formed in group D. X-ray and histological examination showed that the repaired results of defects in the group A were better than those in others groups evidently in extracellular matrix degradation, new bone remodeling and marrow cavity rebuilding at 4 and 8 weeks postoperatively. At 12 weeks postoperatively, the cortical bone became mature lamellar bone, new bone remodeling was complete and marrow cavity was smooth in group A. Only proximal end of defects showed that marrow cavity was refolded partially in group B. The continuous callus could be observed in bone defect, and no obvious marrow cavity remodeling was observed in group C. Lots of fibrous connective tissue filled in defect and bone nonunion was shown in group D. There was no significant difference in the damage compress loading of repaired radius between groups A, B and D (P>0.05), but there was significant difference between groups C and D (P<0.01). CONCLUSION: These results demonstrate that Cbfal gene modified MSCs combined with acellular bone extracellular matrix can be used to repair rabbit radial defects.

Animals↗
PubMed2005

Fitness consequences of Anopheles gambiae population hybridization.

BACKGROUND: The use of transgenic mosquitoes with parasite inhibiting genes has been proposed as an integral strategy to control malaria transmission. However, release of exotic transgenic mosquitoes will bring in novel alleles along with parasite-inhibiting genes that may have unknown effects on native populations. Thus it is necessary to study the effects and dynamics of fitness traits in native mosquito populations in response to the introduction of novel genes. This study was designed to evaluate the dynamics of fitness traits in a simulation of introduction of novel alleles under laboratory conditions using two strains of Anopheles gambiae: Mbita strain from western Kenya and Ifakara strain from Tanzania. METHODS: The dynamics of fitness traits were evaluated under laboratory conditions using the two An. gambiae strains. These two geographically different strains were cross-bred and monitored for 20 generations to score fecundity, body size, blood-meal size, larval survival, and adult longevity, all of which are important determinants of the vector's potential in malaria transmission. Traits were analysed using pair-wise analysis of variance (ANOVA) for fecundity, body size, and blood-meal size while survival analysis was performed for larval survival and adult longevity. RESULTS: Fecundity and body size were significantly higher in the progeny up to the 20th generation compared to founder strains. Adult longevity had a significantly higher mean up to the 10th generation and average blood-meal size was significantly larger up to the 5th generation, indicating that hybrids fitness is enhanced over that of the founder strains. CONCLUSION: Hybridization of the two mosquito populations used in this study led to increased performance in the fitness traits studied. Given that the studied traits are important determinants of the vector's potential to transmit malaria, these results suggest the need to release genetically modified mosquitoes that have the same or very similar backgrounds to the native populations.

Animals↗