Thursday, 27 December 2007

Cardiac stem cell therapy closer to reality

Cardiac stem cell therapy closer to reality Thursday, 27 December 2007 Since the year 2000, much has been learned about the potential for using transplanted cells in therapeutic efforts to treat varieties of cardiac disorders. With many questions remaining, the current issue of CELL TRANSPLANTATION (Vol.16 No. 9), The Proceedings of the Third Annual Conference on Cell Therapy for Cardiovascular Disease, presents research aimed at answering some of them. Eleven papers were included in this issue; the four below represent a sample. Bench to Bedside “Cardiac stem cell therapy involves delivering a variety of cells into hearts following myocardial infarction or chronic cardiomyopathy,” says Amit N. Patel, MD, MS, director of cardiac cell therapy at the University of Pittsburgh Medical Center and lead author of an overview and introductory article, Cardiac Stem Cell Therapy from Bench to Bedside. “Many questions remain, such as what types of cells may be most efficacious. Questions about dose, delivery method, and how to follow transplanted cells once they are in the body and questions about safety issues need answers. The following studies, contribute to the growing body of data that will move cell transplantation for heart patients closer to reality.” According to Patel, special editor for this issue, suitable sources of cells for cardiac transplant will depend on the types of diseases to be treated. For acute myocardial infarction, a cell that reduces myocardial necrosis and augments vascular blood flow will be desirable. For heart failure, cells that replace or promote myogenesis, reverse apoptotic mechanisms and reactivate dormant cell processes will be useful. “Very little data is available to guide cell dosing in clinical studies,” says Patel. “Pre-clinical data suggests that there is a dose-dependent improvement in function.” Patel notes that the availability of autologous (patient self-donated) cells may fall short. Determining optimal delivery methods raise issues not only of dose, but also of timing. Also, assessing the fate of injected cells is “critical to understanding mechanisms of action.” Will cells home to the site of injury? Labelling stem cells with durable markers will be necessary and new tracking markers may need to be developed.

Improved cell survival drugs Adult bone marrow-derived mesenchymal stem cells (MSCs) have shown great signalling and regenerative properties when delivered to heart tissues following a myocardial infarction (MI). However, the poor survival of grafted cells has been a concern of researchers. Given the poor vascular supply after a heart attack and an active inflammatory process, grafted cells survive with difficulty. Transmyocardial revascularisation (TMR), a process by which channels are created in heart tissues by laser or other means, can enhance oxygenated blood supply. “We hypothesized that using TMR as a scar pre-treatment to cell therapy might improve the microenvironment to enhance cell retention and long-term graft success,” said Amit N. Patel, lead author of a study titled Improved Cell Survival in Infarcted Myocardium Using a Novel Combination Transmyocardial Laser and Cell Delivery System. “TMR may act synergistically with signalling factors to have a more potent effect on myocardial remodelling.” Patel and colleagues, who used a novel delivery system to disperse cells in the TMR-generated channels in an animal model, report significant cell survival in the TMR+Cell group versus Cells or TMR alone. The researchers speculated that there was an increase in local production of growth factors that may have improved the survival of transplanted cells. Contact: Amit N. Patel, MD, MS, director of cardiac cell therapy, University of Pittsburgh Medical Center, McGowan Institute of Regenerative Medicine, 200 Lothrop Street – PUH C-700, Pittsburgh, PA 15213 TEL: 412-648-6411 Email:
Stem cells depolarize Recent studies have suggested that there are stem cells in the heart. In this study, researchers engineered mesenchymal stem cells (MSC) to over express stromal cell-derived factor-1 (SDF-1), a chemokine. “Our study suggests that the prolongation of SDF-1 expression at the time of an acute myocardial infarction (AMI) leads to the recruitment of what may be an endogenous stem cell in the heart,” says Marc Penn, MD, PhD, director of the Skirball Laboratory for Cardiovascular Cellular Therapeutics at the Cleveland Clinic Foundation. “These cells may contribute to increased contractile function even in their immature stage.” In the study titled SDF-1 Recruits Cardiac Stem Cell Like Cells that Depolarize in Vivo, researchers concluded that there is a natural but inefficient stem cell-based repair process following an AMI that can be manipulated through the expression of key molecular pathways. The outcome of this inefficient repair can have a significant impact on the electrical and mechanical functions of the surviving myocardium. Contact: Marc Penn, MD, PhD, director, Skirball Laboratory for Cardiovascular Cellular Therapeutics, NE3, Departments of Cardiovascular Medicine and Cell Biology, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, Ohio, 44195. TEL: 216-444-7122 Email:
Grafting bioartifical myocardium for myocardial assistance While the object of cell transplantation is to improve ventricular function, cardiac cell transplantation has had limited success because of poor graft viability and low cell retention. In a study carried out by a team of researchers from the Department of Cardiovascular Surgery, Pompidou Hospital, a matrix seeded with bone marrow cells (BMC) was grafted onto the infarcted ventricle to help support and regenerate post-ischemic lesions. “Our study demonstrated that bone marrow cell therapy associated with the surgical implantation onto the epicardium of a cell-seeded collagen type 1 matrix prevented myocardial wall thinning, limited post-ischemic remodelling and improved diastolic function,” says Juan Chachques, MD, PhD, lead author for Myocardial Assistance by Grafting a New Bioartificial Upgraded Myocardium (MAGNUM Clinical Trial): One year follow-up. “The use of the biomaterial appears to create a micro atmosphere where both exogenous and endogenous cells find an optimal microenvironment to repair tissues and maintain low scar production,” explains Chachques. According to Chachques, the favourable effects may be attributed to several mechanisms. The BMC seeded in the collagen matrix may be incorporated into the myocardium through epicardial channels created at the injection sites. Too, the cell-seeded matrix may help prevent apoptosis. “This biological approach is attractive because of its potential for aiding myocardial regeneration with a variety of cell types,” concluded Chachques. Those cell types include skeletal myoblasts, bone marrow-derived mesenchymal stem cells, circulating blood-derived progenitor cells, endothelial and mesothelial cells, adipose tissue stem cells and, potentially, embryonic stem cells. Contact: Juan C. Chachques, MD, PhD, Department of Cardiovascular Surgery, Pompidou Hospital, 20 rue Leblanc, 75015 Paris, France. TEL: ++33613144398 Email:
“Cardiac stem cell repair is one of the most important new areas of research today,” says Cell Transplantation editor Paul Sanberg, PhD, DSc. “This special issue illustrates important new findings and the significant efforts being taken to develop these therapies and move them from the scientist’s bench to the bedside where in clinical practice they can make a difference in the lives of patients.” The editorial offices for CELL TRANSPLANTATION are at the Center of Excellence for Aging and Brain Repair, College of Medicine, the University of South Florida. Contact: Paul Sanberg, PhD., DSc at ......... ZenMaster
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Thursday, 20 December 2007

California Company Creates Parthenogenetic hESC Lines

California Company Creates Parthenogenetic hESC Lines Thursday, 20 December 2007 Scientists at California-based International Stem Cell Corporation (ISCO) have created unique human stem cell lines that make them easily “immune matched” to human beings and could enable the creation of a bank of stem cells that could be used, without rejection, by a majority of the different people and races of the world. Akin to the concept of finding multiple “universal Type O blood donors”, the discovery is significant because it would eliminate the need for harsh immune suppression drugs currently used for cell transplant therapy. This may open the door to cell transplant therapy for diseases such as juvenile diabetes where the use of immune suppressant drugs is harmful to the patient. The findings are outlined in a scientific peer review paper entitled “HLA Homozygous Stem Cell Lines Derived from Human Parthenogenetic Blastocysts” which was announced in the December 19, 2007 online edition of Cloning and Stem Cells Journal. Of four unique human stem cell lines created, one line identified as hpSC-Hhom-4 was found to be a match with common immune types found in various races across the United States, opening the door to wide application in human therapeutics. The paper reports that for the Hhom-4 line, for example, therapeutic applications could be beneficial for tens of millions of people in the United States alone. “We are excited about this finding as it moves us closer to being able to cross-match stem cells for human transplant and build a true stem cell bank that could offer on-demand delivery of stem cells matched to a patient’s own immune system and eliminate the need for immunosuppressant drugs,” said Jeff Krstich, CEO of International Stem Cell Corporation. “Our intent is to begin clinical safety studies in animals immediately and utilize these hpSC-Hhom (or Hhom) cell lines to advance the field of regenerative medicine, as well as to commercialize our cells for cell transplant therapies.” One of the greatest risks with all transplants is immune rejection, notes Jeffrey Janus, Director of Scientific Research and co-author of the paper. “Immune suppressant drugs are usually required that result in a precarious balance that involves intentional compromise of the patient’s immune system to keep the body from rejecting the transplant, while still maintaining an immune system strong enough to defend against opportunistic infections and disease.” It is far more complicated in children, he added. “Children are more sensitive to the harsh effects of immune-suppressant drugs, thereby reducing therapeutic options and positive outcomes.” Transplant-based stem cell therapies face the same immune matching challenges as those faced by patients undergoing tissue and organ transplants. This makes ISCO’s creation of the Hhom stem cell lines a significant step toward achieving successful donor stem cell transplants. These new stem cell lines were created by ISCO lead scientist Dr. Elena Revazova using a process called “parthenogenesis”, which utilizes unfertilized human eggs and doesn’t destroy fertilized human embryos. International Stem Cell Corporation on June 27, 2007 announced that Dr. Revazova, one of the world’s leading cell biologists, had led a team in the first deliberate creation of human parthenogenetic stem lines. That breakthrough was outlined in a peer review paper entitled “Patient-Specific Stem Cell Lines Derived from Human Parthenogenetic Blastocysts”, and published in Cloning and Stem Cells Journal. That process then led to the current creation of the Hhom cell lines, which represent a “next major step” advancement of ISCO’s original parthenogenetic breakthrough. Data presented shows that the four new stem cell lines function similarly to those derived from fertilized human embryos and have the capacity to differentiate into the three germ layers of the body, meaning they have the ability to become any human cell type. Future work is focused on differentiating the Hhom cell lines into therapeutically useful cells. Although these Hhom lines are virtually animal contaminant free — a distinction likely to be critical for meeting Federal Drug Administration (FDA) approval for human clinical trials — the biggest advantage is that these parthenogenetically-derived stem cells have a simplified genetic code in the critical “HLA region” of the DNA, the region that gives a cell its immune profile to the outside world. The overall result produces a cell that is more easily matched with the immune systems of a far greater percentage of a population group. The paper reports that “with proper selection of oocyte donors according to HLA haplotype, and FDA approved manufacturing protocols, it is possible to generate a bank of cell lines whose tissue derivatives collectively could be MHC-matched with a significant number of individuals.” In explaining how the cell lines may be applied in populations worldwide, the paper notes: “It has been suggested that a panel of only ten HLA homozygous human stem cell lines selected for common types can provide a complete HLA-A, HLA-B and HLA-DR match for 37.7% of United Kingdom recipients, and a beneficial match for 67.4%.” In addressing the US population, the paper notes, “…calculations suggest that there are close to 200 common haplotypes per racial group. The hpSC-Hhom-4 line carries one of the most common haplotypes.” “We believe that Hhom lines are ideally suited for establishing a repository — a stem cell bank — of differentiated cells and tissues HLA-matched to population groups, which could be available for immediate clinical application,” added Krstich. “ISCO’s discovery significantly reduces the number of necessary stem cell lines needed to treat vast numbers of people. Moreover, the process is relatively efficient and reproducible.” The paper reports that aside from regenerative therapy, “a repository of cells and tissues derived from Hhom lines may be invaluable in the treatment of genetic disorders, “…including Alzheimer’s disease, diabetes, Graves disease, haemophilia, Huntington’s Disease, muscular dystrophy, Parkinson’s disease, sickle cell anaemia, Phenylketonuria-PKU and Severe Combined Immune Deficiency (SCID). Scientists must first change or “differentiate” the Hhom stem cells into the proper cell type to cure these diseases, but the Hhom lines should provide the best starting point for these studies. ......... See also: Chinese Groups Make Parthenogenetic hESCs Comments: More new lines of human parthenogenetic embryonic stem cells Cell Research (2008) 18:215–217. doi: 10.1038/cr.2008.19; published online 4 February 2008 ......... ZenMaster

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Wednesday, 19 December 2007

The Latest About Synthetic Life

Read The Latest About Synthetic Life Synthetic DNA on the Brink of Yielding New Life Forms Washington Post - Monday, December 17, 2007 ......... ZenMaster For more on stem cells and cloning, go to CellNEWS at

Thursday, 13 December 2007

Chinese Groups Make Parthenogenetic hESCs

Two Chinese Groups Make Parthenogenetic hESCs Thursday, 13 December 2007 Two Chinese groups report this week, in the journal Cell Research, that they have obtained homozygous human ESC lines from a parthenogenetic oocyte, a process by which an oocyte is activated to develop without fusing with a sperm. Homozygous human embryonic stem cells (hESCs) are thought to be better cell sources for hESC banking because their histocompatibility would make it much more easy of finding matches for certain populations with relatively smaller groups of cell lines. Therefore they will be an important source of histocompatible cells and tissues for cell therapy in the future. The first group is lead by Guangxiu Lu at Central South University in Changsha, China. She has for a long period of time already worked with embryonic stem cells, and even claimed to have produced cloned human embryos several years ago. The other group is Shu-zhen Huang’s at the Institute of Medical Genetics, Shanghai Jiao Tong University School of Medicine, together with Qi Zhou’s laboratory in Beijing at the State Key Laboratory of Reproductive Biology, Institute of Zoology, the Chinese Academy of Sciences. Shu-zhen Huang is known for having created human-rabbit mixed embryos some years ago. Guangxiu Lu’s groups describe one cell line, while the other group succeeded to make two different cell lines. Both groups has carefully and detailed characterized their cells and determined they are of parthenogenetic origin by several techniques. References: A highly homozygous and parthenogenetic human embryonic stem cell line derived from a one-pronuclear oocyte following in vitro fertilization procedure Ge Lin, Qi OuYang, Xiaoying Zhou, Yifan Gu, Ding Yuan, Wen Li, Gang Liu, Tiancheng Liu & Guangxiu Lu Cell Res 2007 17: 999-1007; 10.1038/cr.2007.97 Derivation of human embryonic stem cell lines from parthenogenetic blastocysts Qingyun Mai, Yang Yu, Tao Li, Liu Wang, Mei-jue Chen, Shu-zhen Huang, Canquan Zhou & Qi Zhou Cell Res 2007 17: 1008-1019; 10.1038/cr.2007.102 Comments: More new lines of human parthenogenetic embryonic stem cells Cell Research (2008) 18:215–217. doi: 10.1038/cr.2008.19; published online 4 February 2008 ......... ZenMaster

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Embryonic Stem Cells Repair Heart

Scientists overcome obstacles to embryonic stem cell heart repair Thursday, 13 December 2007 Scientists funded by the Biotechnology and Biological Sciences Research Council (BBSRC) at Imperial College London have overcome two significant obstacles on the road to harnessing stem cells to build patches for damaged hearts. Presenting the research at a UK Stem Cell Initiative conference today (13 December) in Coventry, research leader Professor Sian Harding will explain how her group have made significant progress in maturing beating heart cells (cardiomyocytes) derived from embryonic stem cells and in developing the physical scaffolding that would be needed to hold the patch in place in the heart in any future clinical application. From the outset the Imperial College researchers have been aiming to solve two problems in the development of a stem cell heart patch. The first is undesirable side effects, such as arrhythmia, that can result from immature and undeveloped cardiomyocytes being introduced to the heart. The second is the need for a scaffold that is biocompatible with the heart and able to hold the new cardiomyocytes in place while they integrate into the existing heart tissue. Matching the material to human heart muscle is also hoped to prevent deterioration of heart function before the cells take over. Professor Harding will tell the conference that the stem cell team, led by Dr Nadire Ali, co-investigator on the grant, have managed to follow beating embryonic stem cell-derived cardiomyocytes for up to seven months in the laboratory and demonstrate that these cells do mature. In this period the cells have coordinated beating activity, and they adopt the mature controls found in the adult heart by approximately four months after their generation from embryonic stem cells. These developed cardiomyocytes will then be more compatible with adult heart and less likely to cause arrhythmias. The team have also overcome hurdles in the development of a biocompatible scaffold. Working closely with a group of biomaterial engineers, led by Dr Aldo Boccaccini and Dr Qizhi Chen, co-investigators on the grant, in the Department of Materials, Imperial College London, they have developed a new biomaterial with high level of biocompatibility with human tissue, tailored elasticity and programmable degradation. The latter quality is important as any application in the heart needs to be able to hold cells in place long enough for them to integrate with the organ but then degrade safely away. The researchers have found that their material, which shares the elastic characteristics of heart tissue, can be programmed to degrade in anything from two weeks upwards depending on the temperatures used during synthesis. Professor Harding said: “Although we are still some way from having a treatment in the clinic we have made excellent progress on solving some of the basic problems with stem cell heart therapies. The work we have done represents a step forward in both understanding how stem cell-derived developing heart cells can be matured in the laboratory and how materials could be synthesised to form a patch to deliver them to damaged areas of the heart.” “A significant amount of hard work and research remains to be done before we will see this being used in patients but the heart is an area where stem cell therapies offer promise. We know that the stem cell-derived cardiomyocytes will grow on these materials, and the next step is to see how the material and cell combination behave in the long term.” Professor Nigel Brown, BBSRC Director of Science and Technology, commented: “This research shows that although embryonic stem cell therapies are still some way away from the clinic, progress is being made on the basic biological developments. As with all new biomedical applications, an understanding of the underpinning fundamental science is essential to successfully moving forward.” Note: An image of human embryonic stem cell derived cardiomyocytes and video footage of beating heart stem cells in culture are available to download from BBSRC’s website. ......... ZenMaster

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Wednesday, 12 December 2007

Stem cells for Duchenne muscular dystrophy?

Reprogrammed human adult stem cells rescue diseased muscle in mice Wednesday, 12 December 2007 Scientists report that adult stem cells isolated from humans with muscular dystrophy can be genetically corrected and used to induce functional improvement when transplanted into a mouse model of the disease. The research, published by Cell Press in the December issue of Cell Stem Cell, represents a significant advance toward the future development of a gene therapy that uses a patient’s own cells to treat this devastating muscle-wasting disease. Duchenne muscular dystrophy (DMD) is a hereditary disease caused by a mutation in the gene that codes for a muscle protein called dystrophin. Dystrophin is a key structural protein that helps to keep muscle cells intact. DMD is characterized by a chronic degeneration of skeletal muscle cells that leads to progressive muscle weakness. Although intense research has focused on finding a way to replace the defective dystrophin protein, at this time there is no cure for DMD. A research group led by Dr. Yvan Torrente from the University of Milan used a combination of cell- and gene-based therapy to isolate adult human stem cells from DMD patients and engineer a genetic modification to correct the dystrophin gene. “Use of the patient’s own cells would reduce the risk of implant rejection seen with transplantation of normal muscle-forming cells,” explains Dr. Torrente. Muscle stem cells, identified by expression of the CD133 surface marker, were isolated from normal and dystrophic human blood and skeletal muscle. The isolated human muscle progenitors were implanted into the muscles of mice and were successfully recruited into muscle fibers. As expected, the CD133+ cells isolated from DMD patients expressed the mutated gene for dystrophin and gave rise to muscle cells that resembled muscle fibers in DMD patients. The researchers then used a sophisticated genetic technique to repair the mutated dystrophin gene in the isolated DMD CD133+ cells so that dystrophin synthesis was restored. Importantly, intramuscular or intra-arterial delivery of the genetically corrected muscle cell progenitors resulted in significant recovery of muscle morphology, function, and dystrophin expression in a mouse model of muscular dystrophy. “These data demonstrate that genetically engineered blood or muscle-derived CD133+ cells represent a possible tool for future stem cell-based autograft applications in humans with DMD,” says Dr. Torrente. The authors caution that significant additional work needs to be done prior to using this technology in humans. “Additional research will substantially enhance our understanding of the mechanisms underlying this effect and may lead to the improvement of gene and cell therapy strategies for DMD.” ......... ZenMaster

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Tuesday, 11 December 2007

More 'functional' DNA in genome than previously thought

More 'functional' DNA in genome than previously thought Tuesday, 11 December 2007 Surrounding the small islands of genes within the human genome is a vast sea of mysterious DNA. While most of this non-coding DNA is junk, some of it is used to help genes turn on and off. As reported online this week in Genome Research, Hopkins researchers have now found that this latter portion, which is known as regulatory DNA and contributes to inherited diseases like Parkinson’s or mental disorders, may be more abundant than we realize. By conducting an exhaustive analysis of the DNA sequence around a gene required for neuronal development, Andrew McCallion, Ph.D., an assistant professor in the McKusick-Nathans Institute of Genetic Medicine, and his team found that current computer programs that scan the genome looking for regulatory DNA can miss more than 60 percent of these important DNA regions. The current methods find regulatory sequences by comparing DNA from distantly related species, under the theory that functionally important regions will appear more similar in sequence than non-functional regions. “The problem with this approach, we have discovered,” says McCallion, “is that it’s often throwing the baby out with the bath water. So while we believe sequence conservation is a good method to begin finding regulatory elements, to fully understand our genome we need other approaches to find the missing regulatory elements.” McCallion had suspected that using sequence conservation would overlook some regulatory DNA, but to see how much, he set up a small pilot project looking at the phox2b gene; he chose this gene both because of its small size and his interest in nerve development (phox2b is involved in forming part of the brain associated with stress response as well as nerves that control the digestive system). The researchers created what they call a “tiled path,” cutting up the DNA sequence around the phox2b gene into small pieces, then inserted each piece into zebrafish embryos along with a gene for a fluorescent protein. If a phox2b fragment was a regulatory element, then it would cause the protein to glow. By watching the growing fish embryos - which have the advantage of being transparent - the researchers could see which pieces were regulators. They uncovered a total of 17 discrete DNA segments that had the ability to make fish glow in the right cells. The team then analyzed the entire region around the phox2b gene using the five commonly used computer programs that compute sequence conservation; these established methods picked up only 29 percent to 61 percent of the phox2b regulators McCallion identified in the zebrafish experiments. “Our data supports the recent NIH encyclopaedia of DNA elements project, which suggests that many DNA sequences that bind to regulatory proteins are in fact not conserved,” says McCallion. “I hope this pilot shows that these types of analyses can be worthwhile, especially now that they can be done quickly and easily in zebrafish.” McCallion is now planning a larger study of other neuronal genes. “I think we are only starting to realize the importance and abundance of regulatory elements; by regulating the gene activity in each cell they help create the diverse range of cell types in our body.” ......... ZenMaster

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Friday, 7 December 2007

Reprogrammed adult cells treat sickle-cell anaemia in mice

Proof of principle for therapeutic use of induced pluripotent stem cells Friday, 07 December 2007 Mice with a human sickle-cell anaemia disease trait have been treated successfully in a process that begins by directly reprogramming their own cells to an embryonic-stem-cell-like state, without the use of eggs. This is the first proof-of-principle of therapeutic application in mice of directly reprogrammed “induced pluripotent stem” (iPS) cells, which recently have been derived in mice as well as humans. The research, reported in Science Express online on December 6, was carried out in the laboratory of Whitehead Member Rudolf Jaenisch. The iPS cells were derived using modifications of the approach originally discovered in 2006 by the Shinya Yamanaka laboratory at Kyoto University. The scientists studied a therapeutic application of iPS cells with the sickle-cell anaemia model mouse developed by the laboratory of Tim Townes of the University of Alabama at Birmingham. Sickle-cell anaemia is a disease of the blood marrow caused by a defect in a single gene. The mouse model had been designed to include relevant human genes involved in blood production, including the defective version of that gene. To create the iPS cells, the scientists started with cells from the skin of the diseased mice, explains lead author Jacob Hanna, a postdoctoral researcher in the Jaenisch lab. These cells were modified by a standard lab technique employing retroviruses customized to insert genes into the cell’s DNA. The inserted genes were Oct4, Sox2, Lif4 and c-Myc, known to act together as master regulators to keep cells in an embryonic-stem-cell-like state. iPS cells were selected based on their morphology and then verified to express gene markers specific to embryonic stem cells. To decrease or eliminate possible cancer in the treated mice, the c-Myc gene was removed by genetic manipulation from the iPS cells. Next, the researchers followed a well-established protocol for differentiating embryonic stem cells into precursors of bone marrow adult stem cells, which can be transplanted into mice to generate normal blood cells. The scientists created such precursor cells from the iPS cells, replaced the defective blood-production gene in the precursor cells with a normal gene, and injected the resulting cells back into the diseased mice. The blood of treated mice was tested with standard analyses employed for human patients. The analyses showed that the disease was corrected, with measurements of blood and kidney functions similar to those of normal mice. “This demonstrates that iPS cells have the same potential for therapy as embryonic stem cells, without the ethical and practical issues raised in creating embryonic stem cells,” says Jaenisch. While iPS cells offer tremendous promise for regenerative medicine, scientists caution that major challenges must be overcome before medical applications can be considered. First among these is to find a better delivery system, since retroviruses bring other changes to the genome that are far too random to let loose in humans. “We need a delivery system that doesn’t integrate itself into the genome,” says Hanna. “Retroviruses can disrupt genes that should not be disrupted or activate genes that should not be activated.” Potential alternatives include other forms of viruses, synthesized versions of the proteins created by the four master regulator genes that are modified to enter the cell nucleus, and small molecules, Hanna says. Despite the rapid progress being made with iPS cells, Jaenisch emphasizes that this field is very young, and that it’s critical to continue full research on embryonic stem cells as well. “We wouldn’t have known anything about iPS cells if we hadn’t worked with embryonic stem cells,” says Jaenisch. “For the foreseeable future, there will remain a continued need for embryonic stem cells as the crucial assessment tool for measuring the therapeutic potential of iPS cells.” Reference: Treatment of Sickle-Cell Anaemia Mouse Model with iPS Cells Generated from Autologous Skin Science Express online, December 6, 2007 ......... ZenMaster

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Wednesday, 5 December 2007

Replacing the Cells Lost in Parkinson Disease

Replacing the Cells Lost in Parkinson Disease Wednesday, 05 December 2007 Parkinson disease (PD) is caused by the progressive degeneration of brain cells known as dopamine (DA) cells. Replacing these cells is considered a promising therapeutic strategy. Although DA cell–replacement therapy by transplantation of human foetal mesencephalic tissue has shown promise in clinical trials, limited tissue availability means that other sources of these cells are needed. Now, Ernest Arenas and colleagues at the Karolinska Institute, together with Olle Lindvall’s group at the Wallenberg Neuroscience Center in Lund, Sweden, have identified a new source for DA cells that provided marked benefit when transplanted into mice with a PD-like disease. In the study, DA cells were derived from ventral midbrain (VM) neural stem cells/progenitors by culturing them in the presence of a number of growth factors — FGF2, sonic hedgehog, and FGF8 — and engineering them by transfection to express Wnt5a. This protocol generated 10-fold more DA cells than did conventional FGF2 treatment. These cells exhibited the transcriptional and biochemical profiles and intrinsic electrophysiological properties of midbrain DA cells. Further analysis revealed that these cells initiated substantial cellular and functional recovery when transplanted into mice with PD-like disease. Importantly, the mice did not develop tumours, a potential risk that has precluded the clinical development of embryonic stem cells as a source of DA cells. These data led the authors to suggest that Wnt5a-treated neural stem cells might be an efficient and safe source of DA cells for the treatment of individuals with PD. Reference: Wnt5a-treated midbrain neural stem cells improve dopamine cell replacement therapy in parkinsonian mice J Clin Invest. Published online 2007 December 3. doi: 10.1172/JCI32273. ......... ZenMaster

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Sunday, 2 December 2007

Human embryonic stem cells mend massive skull injury

Human embryonic stem cells mend massive skull injury in mice Sunday, 02 December 2007 Broken skulls can be repaired using cells from human embryos, scientists have shown. Researchers were able to plug holes in the skulls of mice by transplanting human embryonic stem cells (hESCs), which grew into new bone tissue. Although at an early stage, the experiment indicated one way that hESCs, or cells like them, might be used in practical treatments. Healing critical-size defects (defects that would not otherwise heal on their own) in intramembraneous bone, the flat bone type that forms the skull, is a vivid demonstration of new techniques devised by researchers at John Hopkins University to use hESCs for tissue regeneration. Using mesenchymal precursor cells isolated from hESCs, the Hopkins team steered them into bone regeneration by using “scaffolds,” tiny, three-dimensional platforms made from biomaterials. Physical context, it turns out, is a powerful influence on cell fate. Nathaniel S. Hwang, Jennifer Elisseeff, and colleagues at Whitaker Biomedical Engineering Institute, Department of Biomedical Engineering, at John Hopkins demonstrated that by changing the scaffold materials, they could shift mesenchymal precursor cells into either of the body’s osteogenic pathways: intramembraneous, which makes skull, jaw, and clavicle bone; or endochondral, which builds the “long” bones and involves initial formation of cartilage, which is then transformed into bone by mineralization. Mesenchymal precursor cells grown on an all-polymer, biodegradable scaffold followed the endochondral lineage. Those grown on a composite scaffold made of biodegradable polymers and a hard, gritty mineral called hydroxyapatite went to the intramembraneous side. Biomaterial scaffolds provide a three-dimensional framework on which cells can proliferate and differentiate, secrete extracellular matrix, and form functional tissues, says Hwang. In addition, their known composition allowed the researchers to characterize the extracellular micro-environmental cues that drive the lineage specification. The promise of pluripotent embryonic stem cells for regenerative medicine hangs on the development of such control techniques. Left to themselves, hESCs in culture differentiate wildly, forming a highly mixed population of cell types, which is of little use for cell-based therapy or for studying particular lineages. Conventional hESC differentiation protocols rely on growth factors, co-culture, or genetic manipulation, say the researchers. The scaffolds offer a much more efficient method. As a proof of principle, Hwang and colleagues seeded hESC-derived mesenchymal cells onto hydroxyapatite-composite scaffolds and used the resulting intramembraneous bone cells to successfully heal large skull defects in mice. The Hopkins researchers believe that this is the first study to demonstrate a potential application of hESC-derived mesenchymal cells in a musculoskeletal tissue regeneration application. (Presented at American Society for Cell Biology's 47th Annual Meeting in Washington, D.C., Abstract B312 Biomaterials-directed In Vivo Commitment of Mesenchymal Cells Derived from Human Embryonic Stem Cells. N. S. Hwang, S. Varghese, J. Elisseeff; Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA) ......... ZenMaster

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Saturday, 1 December 2007

ESCs produced from fibroblasts without oncogenes

Japanese group make induced pluripotent stem cells from fibroblasts without oncogenes Saturday, 01 December 2007 The Japanese journal Yomiuri Shimbun report that Prof. Shinya Yamanaka from A Kyoto University now have produced induced pluripotent stem cells, or iPS cells, from skin cells of humans and mice without using cancer-causing oncogene c-Myc. The team, led by Prof. Shinya Yamanaka, says its research shows iPS cells produced by their new method are less likely to develop cancer-inducing properties. The group's paper will be published online Saturday by scientific journal Nature Biotechnology. Read more: Stem cell breakthrough made at Kyoto U. The Yomiuri Shimbun - 01 December 2007 Reference: Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts Nature Biotechnology 30 November 2007 doi:10.1038/nbt1374 ......... ZenMaster

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Thursday, 29 November 2007

ESI generate clinical-grade hESC lines

ES Cell International generate six clinical-grade hESC lines Thursday, 29 November 2007 The use of clinical-grade human embryonic stem cells (hESCs) for cell therapy has taken an important step forward. ES Cell International (ESI) has derived the first clinical-grade hESCs by using current Good Manufacturing Practice (cGMP) and Good Tissue Practice (cGTP) respectively, according to an article in the latest issue of "Cell Stem Cell". To hasten the clinical use of hESCs, ESI and the Singapore Stem Cell Bank (SSCB) are currently working out a distribution agreement. This will provide research-grade variants of clinical-grade cell lines to academic researchers at not-for-profit institutes around the world for a fee. ESI will also provide commercial industry players and those who want to conduct clinical trials access to clinical-grade versions of hESCs, under a licence. Reference: The Generation of Six Clinical-Grade Human Embryonic Stem Cell Lines Cell Stem Cell, Vol 1, 490-494, 15 November 2007 ......... ZenMaster

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How Many Genes in the Human Genome?

New Study from Broad Institute Lowers Human Gene Count to 20,500 Thursday, 29 November 2007 A study published online this week in the Proceedings of the National Academy of Sciences indicates that the number of protein-coding genes in the human genome may be much lower than the current estimate of around 24,500 genes. According to the study, published by Michele Clamp and colleagues at the Broad Institute, human gene catalogue’s such as Ensembl, RefSeq, and Vega include many open reading frames that are actually “random occurrences” rather than protein-coding regions — a finding that cuts the number of protein-coding genes in the genome to around 20,500. The Broad team analyzed ORFs for which there is no evidence of evolutionary conservation with mouse or dog. According to the researchers, it has been “broadly suspected” that many of these ORFs are “functionally meaningless,” but there has been no scientific evidence to prove they are not valid genes. “As a result,” they note in the PNAS paper, “the human gene catalogue has remained in considerable doubt.” Clamp and colleagues developed a method to characterize the properties of putative genes that lack cross-species counterparts. By analyzing these non-conserved ORFs alongside the genomes of two primates, the researchers found that they are neither the result of gene innovation in the primate lineage nor the result of gene loss in mouse or dog. This offers “strong evidence” that these non-conserved ORFs are indeed “spurious,” and should be removed from the gene catalogue’s, according to the paper. The Broad team did acknowledge that the study has “certain limitations” that could impact the final gene count. For example, they note, they did not consider 197 putative genes that lie in regions that were omitted from the finished assembly of the human genome. They concede that it’s likely there are additional protein-coding genes yet to be found, but they believe that “the final total is likely to remain under 21,000.” Reference: Distinguishing protein-coding and noncoding genes in the human genome Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0709013104 ......... ZenMaster

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A molecular map for aging

A molecular map for aging in mice and humans Wednesday, 28 November 2007 Researchers at the National Institute of Aging and Stanford University have used gene arrays to identify genes whose activity changes with age in 16 different mouse tissues. The study, published November 30 in PLoS Genetics, uses a newly available database called AGEMAP to document the process of aging in mice at the molecular level. The work describes how aging affects different tissues in mice, and ultimately could help explain why lifespan is limited to just two years in mice. As an organism ages, most tissues change their structure (for example, muscle tissues become weaker and have slow twitch rather than fast twitch fibres), and all tissues are subject to cellular damage that accumulates with age. Both changes in tissues and cellular damage lead to changes in gene expression, and thus probing which genes change expression in old age can lead to insights about the process of aging itself. Previous studies have studied gene expression changes during aging in just one tissue. The new work stands out because it is much larger and more complete, including aging data for 16 different tissues and containing over 5.5 million expression measurements. One noteworthy result is that some tissues (such as the thymus, eyes and lung) show large changes in which genes are active in old age whereas other tissues (such as liver and cerebrum) show little or none, suggesting that different tissues may degenerate to different degrees in old mice. Another insight is that there are three distinct patterns of aging, and that tissues can be grouped according to which aging pathway they take. This result indicates that there are three different clocks for aging that may or may not change synchronously, and that an old animal may be a mixture of tissues affected by each of the different aging clocks. Finally, the report compares aging in mice to aging in humans. Several aging pathways were found to be the same, and these could be interesting because they are relevant to human aging and can also be scientifically studied in mice. Reference: AGEMAP: A gene expression database for aging in mice. PLoS Genet 3(11): e201. ......... ZenMaster

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Tuesday, 27 November 2007

Stem cell therapies for brain more complicated than thought

Stem cell therapies for brain more complicated than thought Tuesday, 27 November 2007 A team of MIT researchers suggests that stem cell therapies for the brain could be much more complicated than previously thought. In a study published in the Public Library of Science (PLoS) Biology on Nov. 13, MIT scientists report that adult stem cells produced in the brain are pre-programmed to make only certain kinds of connections — making it impossible for a neural stem cell originating in the brain to be transplanted to the spinal cord, for instance, to take over functions for damaged cells. Some researchers hope to use adult stem cells produced in the brain to replace neurons lost to damage and diseases such as Alzheimer’s. The new study calls this into question. “It is wishful thinking to hope that adult stem cells will be able to modify themselves so that they can become other types of neurons lost to injury or disease”, said Carlos E. Lois, assistant professor of neuroscience in MIT’s Picower Institute for Leaning and Memory. In developing embryos, stem cells give rise to all the different types of cells that make up the body--skin, muscle, nerve, brain, blood and more. Some of these stem cells persist in adults and give rise to new skin cells, stomach lining cells, etc. The idea behind stem-cell therapy is to use these cells to repair tissue or organs ravaged by disease. To realize this potential, the stem cells have to be “instructed” to become liver cells, heart cells or neurons. The MIT study, which looked only at adult neural stem cells, suggests it will be necessary to learn how to program any kind of stem cell — embryonic, adult or those derived through other means — to produce specific types of functioning neurons. Without this special set of instructions, a young neuron will only connect with the partners for which it was pre-programmed. The adult brain harbours its own population of stem cells that spawn new neurons for life. The MIT study shows that a neural stem cell is irreversibly committed to produce only one type of neuron with a pre-set pattern of connections. This means that a given neuronal stem cell can have only limited use in replacement therapy. “A stem cell that produces neurons that could be useful to replace neurons in the cerebral cortex (the type of neurons lost in Alzheimer's disease) will be most likely useless to replace neurons lost in the spinal cord,” said Lois, who also holds an appointment in MIT’s Department of Brain and Cognitive Sciences. “Moreover, because there are many different types of neurons in the cerebral cortex, it is likely that we will have to figure out how to program stem cells to become many different types of neurons, each of them with a different set of pre-specified connections.” “In the stem cell field, it is generally thought that the main limitation to achieve brain repair is simply for the new neurons to reach a given brain region and to ensure their survival. Once there, it has been assumed that stem cells will ‘know what to do’ and will become the type of neuron that is missing. It seems that is not the case at all. Our experiments indicate that things are much more complicated,” Lois said. Lois and colleagues from MIT’s departments of Brain and Cognitive Sciences and Biology found that the stem cells give rise to neurons that become a very specific neuronal type that is already pre-specified to make a much defined set of connections and not others. Even if the stem cells are transplanted to other parts of the brain, they do not change the type of connections they are programmed to make. “This suggests that we will have to know much more about the different types of neuronal stem cells, and to identify the characteristic features of their progeny,” Lois said. “We may need to have access to many different types of ‘tailored’ stem cells that give rise to many different types of neurons with specific connections. In addition, we may need a combination of several of these tailored stem cells to eventually be able to replace the different types of neurons lost in a given brain region.” ......... ZenMaster

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Researchers find mature heart cell potential in hESCs

UC Davis researchers find evidence of mature heart cell potential in hESCs Finding advances field toward future use of stem cell treatment of end-stage heart disease Tuesday, 27 November 2007 In a new study, UC Davis researchers report the first functional evidence that heart cells derived from human embryonic stem cells exhibit one of the most critical properties of mature adult heart cells, an important biological process called excitation-contraction coupling. The finding gives scientists hope that these cells can one day be coaxed into becoming functionally viable cells safe for transplantation into the damaged hearts of patients with end-stage disease, potentially avoiding the necessity of a heart transplant. Currently, there are nearly 3,000 people on heart transplant lists around the nation, including more than 300 in California. UC Davis research scientist Ronald Li and his colleagues write in their study, “Functional Sarcoplasmic Reticulum for Calcium-Handling of Human Embryonic Stem Cell-Derived Cardiomyocytes: Insights for Driven Maturation,” that they observed cells that had begun the maturation process toward becoming heart cells. The article, available online in Stem Cell Express, will be published in the December issue of the journal Stem Cells. “Previous experiments were able to derive heart cells from human embryonic stem cells,” said Li, who is an associate professor of cell biology and human anatomy at UC Davis School of Medicine and senior author of the study. “... but those cells always remained too immature to be of any therapeutic use and actually could cause lethal arrhythmias in animal models. Now, what we’ve been able to do is push the therapeutic potential of human embryonic stem cells further so that eventually they might be used safely, and with enhanced efficacy, in transplantation cases.” The main function of the heart is to mechanically pump blood in a highly coordinated fashion throughout the body. To do this, heart cells must receive electrical signals and contract in response to those signals. This link, called the excitation-contraction coupling, is dependent on the cells’ ability to move calcium ions across an internal organelle known as sarcoplasmic reticulum, or the so-called “calcium store.” The ability to handle calcium is disrupted in the cells of patients who experience heart failure. For future stem-cell based therapies to work, scientists will need to have heart cells that exhibit mature excitation-contraction coupling. Until now, researchers studying heart cells (also called cardiomyocytes) derived from human embryonic stem cells have been unable to find evidence of functional calcium stores. Li found protein functions that are involved in the early stages of this coupling process. He and his colleagues now plan to move on and engineer the calcium-handling properties in order to enhance contractile properties in cardiomyocytes for both improved safety and functional efficacy. In the current study, Li and his colleagues took human embryonic stem cells and grew them in cultures, allowing them to differentiate, or develop, into heart cells. Once they had these tiny, pulsing masses, the investigators energized the cells with small amounts of electrical current and chemicals, including caffeine. They then measured how the amount of intracellular calcium changed and looked for the presence of proteins and cellular structures known to be involved in excitation-contraction coupling. Li and his colleagues are the first to find evidence of the functional calcium stores for excitation-contraction coupling. They also found four of the seven key proteins that play key roles in handling calcium in the cell, as well as functional sarcoplasmic reticulum. The UC Davis researchers used different cell lines than those utilized in previous studies, which they say may explain why they were able to achieve a breakthrough in their investigation where others had not. The UC Davis group also looked at a smaller number of cells during various stages of development, enabling them to more accurately dissect the different population subsets. The authors said that differences in cell culture and experimental conditions could also account for the results not seen in previous efforts. According to Li, the fact that different cell lines exhibit different potentials for differentiation and maturation underscores the need to develop new and additional stem cell lines in order to advance critical research into potential therapies for patients. “This is a good example of the type of exciting, bench-to-bedside research now under way at UC Davis and the potential it has for new treatments,” said Jan Nolta, director of the UC Davis Stem Cell Program in Sacramento. “As additional embryonic stem cell lines become available for research, we’ll be able to more fully explore the possibilities inherent in this powerful field of bioscience.” Li’s study is a first step toward deriving cardiomyocytes with fully functional contractile properties from human embryonic stem cells. With heart transplants being the current treatment of last resort due to severe shortages of donor organs and the complexity of transplantation, the long term goal of researchers like Li is to come up with alternatives that are both safe and effective. “Our latest study gives us great hope of eventually achieving a breakthrough where stem cell therapy could be used in the types of cases that today require a heart transplant,” concluded Li. Along with Li, co-authors of the paper are Jing Liu, Jidong Fu and David Siu all from UC Davis School of Medicine. The research was funded by the National Institutes of Health, California Institute of Regenerative Medicine, the Croucher Foundation and UC Davis School of Medicine. ......... ZenMaster

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Wednesday, 21 November 2007

Reprogramming of human fibroblasts to ESCs achieved

Reprogramming of human fibroblasts to ESCs achieved Tuesday, 20 November 2007 Scientists have managed to reprogram human skin cells directly into cells that look and act like embryonic stem (ES) cells. The technique makes it possible to generate patient-specific stem cells to study or treat disease without using embryos or oocytes – and therefore could bypass the ethical debates that have plagued the field. The new discovery is being published online today in Cell, in a paper by Shinya Yamanaka of Kyoto University and the Gladstone Institute for Cardiovascular Disease in San Francisco, and in Science, in a paper by James Thomson and his colleagues at the University of Wisconsin. While both groups used just four genes to reprogram human skin cells, two of the four genes (Oct3/4, Sox2, c-Myc, and Klf4) used by the Japanese scientists were different from two of the four used by the American group (Oct4, Sox2, Nanog, and Lin28). All the genes in question, though, act in a similar way – they are master regulator genes whose role is to turn other genes on or off. A limitation is that the scientists use a retrovirus to insert the genes into the cells’ chromosomes. Retroviruses slip genes into chromosomes at random, and sometimes cause mutations that can make normal cells turn into cancers during this process. In addition, one of the genes that the Japanese scientists insert, the c-Myc gene, in fact is a cancer gene. “It is only a matter of time until retroviruses are not needed,” Dr. Douglas Melton, co-director of the Stem Cell Institute at Harvard University predicted. “Anyone who is going to suggest that this is just a side show and that it won’t work is wrong,” Dr. Melton said. The new discovery was preceded by work in mice. Last year, Dr. Yamanaka published a paper showing that he could add four genes to mouse cells and turn them into mouse embryonic stem cells (see Turning Adult Cells Embryonic). This publication last year set off what became an international race to repeat the work with human cells. “Dozens, if not hundreds of labs, have been attempting to do this,” said Dr. George Daley, associate director of the stem cell program at Children’s Hospital in Boston. In this new work, Yamanaka and his colleagues used a retrovirus to ferry into adult cells the same four genes they had previously employed to reprogram mouse cells: Oct3/4, Sox2, Klf4, and c-Myc. They reprogrammed cells taken from the facial skin of a 36-year-old woman and connective tissue from a 69-year-old man. Roughly one iPS (induced pluripotent stem) cell line was produced for every 5000 cells the researchers treated with the technique, an efficiency that enabled them to produce several cell lines from each experiment. Thomson's team started from scratch, identifying its own list of 14 candidate reprogramming genes. The team used a systematic process of elimination to identify four factors: Oct3 and Sox2, as Yamanaka used, and two different genes, Nanog and Lin28. The group reprogrammed cells from foetal skin and from the foreskin of a newborn boy. The researchers were able to transform about one in 10,000 cells, but still enough to create several cell lines from a single experiment. Although promising, both techniques share a downside. The retroviruses used to insert the genes could cause tumours in tissues grown from the cells. The crucial next step, everyone agrees, is to find a way to reprogram cells by switching on the genes rather than inserting new copies. The field is moving quickly toward that goal. "It is not hard to imagine a time when you could add small molecules that would tickle the same networks as these genes" and produce reprogrammed cells without genetic alterations, said Dr. Douglas Melton of Harvard University. Once the kinks are worked out, "the whole field is going to completely change," said stem cell researcher Jose Cibelli of Michigan State University in East Lansing. "People working on ethics will have to find something new to worry about." See also: UW-Madison scientists also guide human skin cells to embryonic like state Yamanaka Turns Human Fibroblasts to ESC-like Cells Turning Adult Cells Embryonic How to Make Stem Cells Stay Growing ......... ZenMaster

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Tuesday, 20 November 2007

UW-Madison scientists also guide human skin cells to embryonic like state

UW-Madison scientists guide human skin cells to embryonic state Tuesday, 20 November 2007 In a paper published in the online edition of the journal Science, a team of University of Wisconsin-Madison researchers reports the genetic reprogramming of human skin cells to create cells indistinguishable from embryonic stem cells. The finding is not only a critical scientific accomplishment, but potentially remakes the tumultuous political and ethical landscape of stem cell biology as human embryos may no longer be needed to obtain the blank slate stem cells capable of becoming any of the 220 types of cells in the human body. Perfected, the new technique would bring stem cells within easy reach of many more scientists as they could be easily made in labs of moderate sophistication, and without the ethical and legal constraints that now hamper their use by scientists. The new study was conducted in the laboratory of UW-Madison biologist James Thomson, the scientist who first coaxed stem cells from human embryos in 1998. It was led by Junying Yu of the Genome Center of Wisconsin and the Wisconsin National Primate Research Center. "The induced cells do all the things embryonic stem cells do," explains Thomson, a professor of anatomy in the University of Wisconsin School of Medicine and Public Health. "It's going to completely change the field." In addition to exorcising the ethical and political dimensions of the stem cell debate, the advantage of using reprogrammed skin cells is that any cells developed for therapeutic purposes can be customized to the patient. "They are probably more clinically relevant than embryonic stem cells," Thomson explains. "Immune rejection should not be a problem using these cells." An important caveat, Thomson notes, is that more study of the newly-made cells is required to ensure that the "cells do not differ from embryonic stem cells in a clinically significant or unexpected way, so it is hardly time to discontinue embryonic stem cell research." The successful isolation and culturing of human embryonic stem cells in 1998 sparked a huge amount of scientific and public interest, as stem cells are capable of becoming any of the cells or tissues that make up the human body. The potential for transplant medicine was immediately recognized, as was their promise as a window to the earliest stages of human development, and for novel drug discovery schemes. The capacity to generate cells that could be used to treat diseases such as Parkinson's, diabetes and spinal cord injuries, among others, garnered much interest by patients and patient advocacy groups. But embryonic stem cells also sparked significant controversy as embryos were destroyed in the process of obtaining them, and they became a potent national political issue beginning with the 2000 presidential campaign. Since 2001, a national policy has permitted only limited use of some embryonic stem cell lines by scientists receiving public funding. In the new study, to induce the skin cells to what scientists call a pluripotent state, a condition that is essentially the same as that of embryonic stem cells, Yu, Thomson and their colleagues introduced a set of four genes,Oct4, Sox2, NANOG, and LIN28, into human fibroblasts, skin cells that are easy to obtain and grow in culture. Finding a combination of genes capable of transforming differentiated skin cells to undifferentiated stem cells helps resolve a critical question posed by Dolly, the famous sheep cloned in 1996. Dolly was the result of the nucleus of an adult cell transferred to an oocyte, an unfertilized egg. An unknown combination of factors in the egg caused the adult cell nucleus to be reprogrammed and, when implanted in a surrogate mother, develop into a fully formed animal. The new study by Yu and Thomson reveal some of those genetic factors. The ability to reprogram human cells through well defined factors would permit the generation of patient-specific stem cell lines without use of the cloning techniques employed by the creators of Dolly. "These are embryonic stem cell-specific genes which we identified through a combinatorial screen," Thomson says. "Getting rid of the oocyte means that any lab with standard molecular biology can do reprogramming without difficulty to obtain oocytes." Although Thomson is encouraged that the new cells will speed new cell-based therapies to treat disease, more work is required, he says, to refine the techniques through which the cells were generated to prevent the incorporation of the introduced genes into the genome of the cells. In addition, to ensure their safety for therapy, methods to remove the vectors, the viruses used to ferry the genes into the skin cells, need to be developed. Using the new reprogramming techniques, the Wisconsin group has developed eight new stem cell lines. As of the writing of the new Science paper, which will appear in the Dec. 21, 2007 print edition of the journal Science, some of the new cell lines have been growing continuously in culture for as long as 22 weeks. Reference: Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells In addition to Yu and Thomson, authors of the new study include Maxim A. Vodyanik, Kim Smuga-Otto, Jessica Antosiewicz-Bourget, Jennifer L. Frane and Igor I. Slukvin, all of UW-Madison; and Shulan Tian, Jeff Nie, Gudrun A. Jonsdottir, Victor Ruotti and Ron Stewart, all of the WiCell Research Institute. See also: Yamanaka Turns Human Fibroblasts to ESC-like Cells Turning Adult Cells Embryonic How to Make Stem Cells Stay Growing ......... ZenMaster

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Yamanaka Turns Human Fibroblasts to ESC-like Cells

Simple recipe turns human skin cells into embryonic stem cell-like cells Tuesday, 20 November 2007 A simple recipe — including just four ingredients — can transform adult human skin cells into cells that resemble embryonic stem cells, researchers report in an immediate early publication of the journal Cell, a publication of Cell Press. The converted cells have many of the physical, growth and genetic features typically found in embryonic stem cells and can differentiate to produce other tissue types, including neurons and heart tissue, according to the researchers. They added, however, that a comprehensive screen of the activity of more than 30,000 genes showed that the so — called “induced pluripotent stem (iPS) cells” are similar, not identical, to embryonic stem cells. "Pluripotent" refers to the ability to differentiate into most other cell types. The chemical cocktail used in the new study is identical to one the team showed could produce iPS cells from adult mouse cells in another Cell report last year. That came as a surprise, said Shinya Yamanaka of Kyoto University in Japan, because human embryonic stem cells differ from those in mice. Those differences had led them to suspect "that some other factors might be required to generate human iPS cells,” he said. The findings are an important step forward in the quest for embryonic stem cell — like cells that might sidestep the ethical stumbling blocks of stem cells obtained from human embryos. He emphasized, however, that it would be “premature to conclude that iPS cells can replace embryonic stem cells.” Embryonic stem cells, derived from the inner cell mass of mammalian blastocysts — balls of cells that develop after fertilization and go on to form a developing embryo — have the ability to grow indefinitely while maintaining pluripotency, the researchers explained. Those properties have led to expectations that human embryonic stem cells might have many scientific and clinical applications, most notably the potential to treat patients with various diseases and injuries, such as juvenile diabetes and spinal cord injury. The use of human embryos, however, faces ethical controversies that hinder the applications of human embryonic stem cells, they continued. In addition, it is difficult to generate patient or disease — specific embryonic stem cells, which are required for their effective application. One way to circumvent these issues is to induce pluripotent status in other cells of the body by direct reprogramming, Yamanaka said. Last year, his team found that four factors, known as Oct3/4, Sox2, c-Myc, and Klf4, could lend differentiated fibroblast cells taken from embryonic or adult mice the pluripotency normally reserved for embryonic stem cells. Fibroblasts make up structural fibers found in connective tissue. Those four factors are “transcription factors,” meaning that they control the activity of other genes. They were also known to play a role in early embryos and embryonic stem cell identity. The researchers have now shown that the same four factors can generate iPS cells from fibroblasts taken from human skin. “From about 50,000 transfected human cells, we obtained approximately 10 iPS cell clones,” Yamanaka said. “This efficiency may sound very low, but it means that from one experiment, with a single ten centimetre dish, you can get multiple iPS cell lines.” The iPS cells were indistinguishable from embryonic stem cells in terms of their appearance and behaviour in cell culture, they found. They also express genetic markers that are used by scientists to identify embryonic stem cells. Human embryonic stem cells and iPS cells display similar patterns of global gene activity. They showed that the converted human cells could differentiate to form three “germ layers” in cell culture. Those primary germ layers in embryos eventually give rise to all the body’s tissues and organs. They further showed that the human iPS cells could give rise to neurons using a method earlier demonstrated for human embryonic stem cells. The iPS cells could also be made to produce cardiac muscle cells, they found. Indeed, after 12 days of differentiation, clumps of cells in the laboratory dishes started beating. The human iPS cells injected under the skin of mice produced tumours after nine weeks. Those tumours contained various tissues including gut — like epithelial tissue, striated muscle, cartilage and neural tissue. They finally showed that iPS cells can also be generated in the same way from other human cells. “We should now be able to generate patient — and disease — specific iPS cells, and then make various cells, such as cardiac cells, liver cells and neural cells,” Yamanaka said. “These cells should be extremely useful in understanding disease mechanisms and screening effective and safe drugs. If we can overcome safety issues, we may be able to use human iPS cells in cell transplantation therapies.” Shinya Yamanaka is also a senior investigator at the Gladstone Institute of Cardiovascular Disease (GICD), an independent, non-profit biomedical research organization affiliated with the University of California, San Francisco. “The rapid application of this approach to human cells has dramatically changed the landscape of stem cell science,” said GICD Director Deepak Srivastava, MD. “Dr. Yamanaka’s work is monumental in its importance to the field of stem cell science and its potential impact on our ability to accelerate the benefits of this technology to the bedside. Not only does this discovery enable more research, it offers a new pathway to apply the benefits of stem cells to human disease.” “Dr. Yamanaka and his group have made yet another extremely important contribution to the stem cell field,” said Richard Murphy, interim president of the California Institute for Regenerative Medicine (CIRM). “Their results open the door to generating alternative sources of pluripotent cells from patients, which is a major step forward. However, much work still needs to be done to fully characterize and understand the capacity of these induced pluripotent cells to study and to treat human diseases.” CIRM’s Murphy added, “Dr. Yamanaka’s work, which uses viral vectors to introduce into cells pluripotency-associated genes, further emphasizes the critical need we have to continue working with naturally occurring human embryonic stem cells, which remain the gold standard against which all alternative sources of human pluripotent stem cells must be tested.” Reference: Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors The researchers include Kazutoshi Takahashi, Kyoto University, in Kyoto, Japan; Koji Tanabe, of Kyoto University, in Kyoto, Japan; Mari Ohnuki, of Kyoto University, in Kyoto, Japan; Megumi Narita, of Kyoto University, in Kyoto, Japan, and the Japan Science and Technology Agency, in Kawaguchi, Japan; Tomoko Ichisaka, of Kyoto University, in Kyoto, Japan, and the Japan Science and Technology Agency, in Kawaguchi, Japan; Kiichiro Tomoda, of the Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA; and Shinya Yamanaka, of Kyoto University, in Kyoto, Japan, the Japan Science and Technology Agency, in Kawaguchi, Japan; and the Gladstone Institute of Cardiovascular Disease, in San Francisco, CA, USA See also: UW-Madison scientists also guide human skin cells to embryonic like state Turning Adult Cells Embryonic How to Make Stem Cells Stay Growing ......... ZenMaster

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Sunday, 18 November 2007

Genetic Testing: Customer DNA analyses

Genetic Testing: Customer DNA Analyses Sunday, 18 November 2007 Three companies have started or are planning services to test customers’ DNA at nearly one million locations (SNP’s) where the human genome is known to vary between individuals. All are offering services to help consumers interpret the information contained in their own genomes. Would you subscribe to such a service? 23andMe Mountain View, Calif. Available now for $999 Services: genotyping 580,000 SNPs using Illumina technology; Gene Journals reporting risk for 20 diseases and physical traits; tools for tracing ancestry and DNA similarity with family and friends; Genome Explorer to provide access to all data to allow customers to compare any published study with their own genotype; will provide referrals to genetic counsellors. Online: deCODE Genetics Reykjavik, Iceland Available now for $985 Services: genotyping one million SNPs using Illumina technology; deCODEme will provide risk reports for about 20 diseases and physical traits; tools for tracing ancestry and DNA similarity with family and friends; genetic counsellors available for consultations. Online: Navigenics Redwood Shores, Calif. Available in 2008 for $2,500 Services: will genotype one million SNPs using Affymetrix technology; health Compass will provide risk reports for about a dozen diseases; results relayed by genetic counsellor. Online: Read more at: My Genome, Myself: Seeking Clues in DNA NY Times - November 17, 2007 ......... ZenMaster

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Dolly Professor Abandons Human Cloning

Dolly Professor Abandons Human Cloning Attempts Sunday, 18 November 2007 The Scottish scientist who created Dolly the sheep more than a decade ago said he is abandoning the cloning technique that he pioneered, according to an interview published Saturday. Professor Ian Wilmut of Edinburgh University, who led the team that created Dolly in 1996, told The Daily Telegraph that he is abandoning cloning to pursue a new technique that can create stem cells without an embryo. He has now embraced a technique developed by Prof Shinya Yamanaka of Kyoto University, Japan, that involves genetically modifying adult cells to make them almost as flexible as stem cells. The research has been conducted on mice. He said: “The work which was described from Japan of using a technique to change cells from a patient directly into stem cells without making an embryo has got so much more potential.” “Even though it's only been described for the mouse, when we were considering which option to pursue, whether to clone or whether to copy the work in Japan, we decided to copy the work in Japan.” Speaking to the Daily Telegraph, Prof Wilmut said: “Before too long we will be able to use the Yamanaka approach to achieve the same, without making embryos. In the long term, direct reprogramming will be more productive.” “I decided a few weeks ago not to pursue nuclear transfer [the method used to create Dolly the sheep]," and he admitted the new method "was easier to accept socially”. Professor Wilmut believes that within five years the new technique could provide a better and ethically more acceptable alternative to cloning embryos for medical research. Now, when Professor Wilmut has decided not to pursue his licence to clone human embryos, an award he was granted just two years ago, one can wonder about some recent actions in his career. A few years ago he was involved in and made plans to collaborate with Hwang Woo-suk on therapeutic cloning before the Korean work was uncovered to be fraudulent. Together with the American Gerald Schatten, they set up The International Stem Cell Bank in Seoul, which became nothing when the fraud was unveiled. None of these experts in cloning realized by themselves that something was wrong with the Korean results. Does he have the technical ability to make human cloning possible? Or does he lack people in his present group who would do the actual cloning work? I doubt he, Professor Wilmut, have the molecular biology expertise needed to be able to repeat Prof Yamanaka experiments on mouse fibroblasts in human counterpart. Only time will tell if this also will be another attempt to ‘build a castles in Spain’ by the Scottish professor. See also: Turning Adult Cells Embryonic ......... ZenMaster

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