The Role of the Federal Government in Overseeing Medical Research

The United States enjoys a unique position among the world community in a number of respects. Although it is not the largest or most populated country in the world, the United States is considered one of the wealthiest. Our significant national wealth affords us with some interesting opportunities. In particular, it allows us to devote a portion of those resources towards causes that we as a nation feel are worthy and significant. For example, such causes include charitable aid programs, in the name of promoting global economic development and world peace. The United States leads in this category as well, donating an annual $27.5 billion in unrestricted charitable foreign aid to promote international economic development through the Office of Development Assistance of the United Nations. Private philanthropy from the United States is even greater, with an estimated$71 billion being given in 2004 from private individuals, foundations, churches, and other organizations. In total, nearly one percent of our national income is given away to individuals, groups, and countries in need around the world. Another one of the ways in which we have chosen to spend (or invest - depending on one\u27s perspective) a portion of our national wealth is in the area of research. Such research covers a broad range of areas, including medical research, technology development, space-related research, material sciences, and a host of other activities. The funding provided to conduct this research comes from both public and private sources. We invest heavily as a nation in government sponsored research across a range of areas. One area in particular rises above the rest in terms of committed resources - medical research. Note that this funding is provided almost entirely to not-for-profit entities, such as colleges, universities, and research institutions, and is distinct from the funding provided by the private sector

Rapid creation of BAC-based human artificial chromosome vectors by transposition with synthetic alpha-satellite arrays

Efficient construction of BAC-based human artificial chromosomes (HACs) requires optimization of each key functional unit as well as development of techniques for the rapid and reliable manipulation of high-molecular weight BAC vectors. Here, we have created synthetic chromosome 17-derived alpha-satellite arrays, based on the 16-monomer repeat length typical of natural D17Z1 arrays, in which the consensus CENP-B box elements are either completely absent (0/16 monomers) or increased in density (16/16 monomers) compared to D17Z1 alpha-satellite (5/16 monomers). Using these vectors, we show that the presence of CENP-B box elements is a requirement for efficient de novo centromere formation and that increasing the density of CENP-B box elements may enhance the efficiency of de novo centromere formation. Furthermore, we have developed a novel, high-throughput methodology that permits the rapid conversion of any genomic BAC target into a HAC vector by transposon-mediated modification with synthetic alpha-satellite arrays and other key functional units. Taken together, these approaches offer the potential to significantly advance the utility of BAC-based HACs for functional annotation of the genome and for applications in gene transfer

First-in-Human Case Study: Multipotent Adult Progenitor Cells for Immunomodulation After Liver Transplantation

Mesenchymal stem cells and multipotent adult progenitor cells (MAPCs) have been proposed as novel therapeutics for solid organ transplant recipients with the aim of reducing exposure to pharmacological immunosuppression and its side effects. In the present study, we describe the clinical course of the first patient of the phase I, dose-escalation safety and feasibility study, MiSOT-I (Mesenchymal Stem Cells in Solid Organ Transplantation Phase I). After receiving a living-related liver graft, the patient was given one intraportal injection and one intravenous infusion of third-party MAPC in a low-dose pharmacological immunosuppressive background. Cell administration was found to be technically feasible; importantly, we found no evidence of acute toxicity associated with MAPC infusions

The Role of the Federal Government in Overseeing Medical Research

The United States enjoys a unique position among the world community in a number of respects. Although it is not the largest or most populated country in the world, the United States is considered one of the wealthiest. Our significant national wealth affords us with some interesting opportunities. In particular, it allows us to devote a portion of those resources towards causes that we as a nation feel are worthy and significant. For example, such causes include charitable aid programs, in the name of promoting global economic development and world peace. The United States leads in this category as well, donating an annual $27.5 billion in unrestricted charitable foreign aid to promote international economic development through the Office of Development Assistance of the United Nations. Private philanthropy from the United States is even greater, with an estimated$71 billion being given in 2004 from private individuals, foundations, churches, and other organizations. In total, nearly one percent of our national income is given away to individuals, groups, and countries in need around the world. Another one of the ways in which we have chosen to spend (or invest - depending on one\u27s perspective) a portion of our national wealth is in the area of research. Such research covers a broad range of areas, including medical research, technology development, space-related research, material sciences, and a host of other activities. The funding provided to conduct this research comes from both public and private sources. We invest heavily as a nation in government sponsored research across a range of areas. One area in particular rises above the rest in terms of committed resources - medical research. Note that this funding is provided almost entirely to not-for-profit entities, such as colleges, universities, and research institutions, and is distinct from the funding provided by the private sector

Efficient assembly of <it>de novo </it>human artificial chromosomes from large genomic loci

<p>Abstract</p> <p>Background</p> <p>Human Artificial Chromosomes (HACs) are potentially useful vectors for gene transfer studies and for functional annotation of the genome because of their suitability for cloning, manipulating and transferring large segments of the genome. However, development of HACs for the transfer of large genomic loci into mammalian cells has been limited by difficulties in manipulating high-molecular weight DNA, as well as by the low overall frequencies of <it>de novo </it>HAC formation. Indeed, to date, only a small number of large (>100 kb) genomic loci have been reported to be successfully packaged into <it>de novo </it>HACs.</p> <p>Results</p> <p>We have developed novel methodologies to enable efficient assembly of HAC vectors containing any genomic locus of interest. We report here the creation of a novel, bimolecular system based on bacterial artificial chromosomes (BACs) for the construction of HACs incorporating any defined genomic region. We have utilized this vector system to rapidly design, construct and validate multiple <it>de novo </it>HACs containing large (100–200 kb) genomic loci including therapeutically significant genes for human growth hormone (HGH), polycystic kidney disease (PKD1) and ß-globin. We report significant differences in the ability of different genomic loci to support <it>de novo </it>HAC formation, suggesting possible effects of <it>cis</it>-acting genomic elements. Finally, as a proof of principle, we have observed sustained ß-globin gene expression from HACs incorporating the entire 200 kb ß-globin genomic locus for over 90 days in the absence of selection.</p> <p>Conclusion</p> <p>Taken together, these results are significant for the development of HAC vector technology, as they enable high-throughput assembly and functional validation of HACs containing any large genomic locus. We have evaluated the impact of different genomic loci on the frequency of HAC formation and identified segments of genomic DNA that appear to facilitate <it>de novo </it>HAC formation. These genomic loci may be useful for identifying discrete functional elements that may be incorporated into future generations of HAC vectors.</p

Cytogenetic analysis of HACs created from unimolecular BAC–HAC vectors

<p><b>Copyright information:</b></p><p>Taken from "Rapid creation of BAC-based human artificial chromosome vectors by transposition with synthetic alpha-satellite arrays"</p><p>Nucleic Acids Research 2005;33(2):587-596.</p><p>Published online 26 Jan 2005</p><p>PMCID:PMC548352.</p><p>© The Author 2005. Published by Oxford University Press. All rights reserved</p> () Dual FISH/immunostaining with anti-CENP-C antibodies (red) and D17Z1 probe (green). () Two-color FISH analysis: D17Z1 probe (green) and 150 kb genomic fragment probe from BAC–HAC vector (red). () Two-color FISH analysis: D17Z1 probe (green) and BAC vector backbone probe (red). () Two-color FISH analysis: D17Z1 probe (green) and telomeric DNA (red). In all panels, DAPI-stained DNA in blue