UW-Madison get NIH grant for ALS stem cell therapy

UW-Madison get $7.2M NIH grant for ALS stem cell therapy Friday, 21 September 2007 With the help of a $7.2 million grant from the National Institutes of Health (NIH), a team of University of Wisconsin-Madison researchers will explore the potential of stem cells and natural growth factors to treat amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. The grant, to be awarded over five years, will fund research aimed at finding novel therapies for treating a debilitating and nearly always fatal condition caused by the withering of motor neurons, the brain cells that control the body's muscles. "This is a great opportunity," says Clive Svendsen, who will direct the project along with UW-Madison neuroscientists Su-Chun Zhang and Gordon S. Mitchell. "There is a lot of synergy between our groups which provide for a lot of overlap that we think will help us get at some of the key issues of ALS." The grant will support a combined cell-based approach to treating ALS, an incurable disease with no proven effective treatments. An estimated 30,000 people in the United States suffer from ALS, and most patients die within three to five years of diagnosis. The new Wisconsin program will utilize both embryonic and foetal stem cells and will explore the possibility of stimulating healthy nerve cells to release growth factors and other chemicals to protect motor neurons. The work will focus on three strategies for promoting healthy motor neurons and hitching new and rescued motor neurons to the muscles they control. The tri-fold approach will be tested in concert in a rat model for ALS. Previous work at UW-Madison has shown that neural cells derived from foetal tissue and engineered to release a key growth factor known as GDNF, a chemical that promotes cell health, protected motor neurons in rats with ALS. However, the rescued nerve cells did not reattach to the muscles they control. Studies to be supported by the new NIH grant will look at transplanting cells engineered to release the GDNF growth factor in combination with motor neurons derived from embryonic stem cells. The hope is there may be some synergistic effect between the two types of cells that not only protect and augment motor neurons in the animal model, but also promote connections with muscles. Zhang, a professor of anatomy in the UW-Madison School of Medicine and Public Health, has previously successfully derived motor neurons from embryonic stem cells. "We're putting them right into the rat model and assessing their effects," explains Svendsen, a prominent stem cell researcher at UW-Madison's Waisman Center. "Motor neurons don't survive very well in transplants, and the hope is the cells in combination with GDNF release may promote a better result." In addition, studies with intriguing potential to address the failure of the respiratory system in ALS, the ultimate cause of death for patients with the disease, are also planned. Despite the fundamental importance of respiratory failure in ALS, it has been little studied. Work by Mitchell, a professor in the UW-Madison School of Veterinary Medicine, will explore the idea of using endogenous mechanisms in the body that seem to afford protection for motor neurons that control the respiratory system until the end stage of the disease. By inducing hypoxia, a condition where tissues are deprived of oxygen, the Wisconsin team hopes to prompt the release of growth factors that seem to have neuroprotective qualities on the respiratory motor neurons that drive the lungs. The new grant, according to Svendsen, is important because it directly addresses key unexplored issues on the frontier of regenerative medicine, an emerging field that seeks to regenerate and replace diseased or damaged tissues and cells. Adopted from a News Release from the UW-Madison. ......... ZenMaster

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Future of personal genomics

As personal genomics stands poised to go mainstream, researchers urge caution Friday, 21 September 2007 Giving Nobel Laureate James Watson his personal genome and Craig Venter publishing his own complete genome was just the beginning. In a future that promises similar information to much of the population, ethicists, scientists and physicians are only beginning to understand and consider the possibilities. In a commentary in today’s issue of the journal Science, four experts ponder the implications of this new technology and information and ask the crucial questions that should be answered before the era of personal genomics comes to pass. They combined their different perspectives to consider what is possible now and in the future. Along with that, they look at the ethical and legal issues that will inevitably arise with such technology. Imagine this: you visit your clinician, undergo genetic testing, and then you are handed a miniature hard drive containing your personal genome sequence, which is subsequently uploaded onto publicly accessible databases. This may sound like science fiction, but it is scientific fact, and it is already happening. University of Alberta researcher Tim Caulfield and co-authors highlight the need to proceed with caution when it comes to personal genomics projects that represent research milestones but are also fraught with ethical, social and clinical implications. Caulfield, who is the Canada Research Chair in Health Law at the U of A and professor and research director in public health sciences, is recognized as one of the foremost experts in health law research in Canada. Scientists predict that within five years DNA sequencing technologies will be affordable enough that personal genomics will be integrated into routine clinical care. Companies are responding by offering their services for ancestry tracing, forensics, nutritional advice and reproductive assistance. It won’t be long before companies are able to offer Facebook-like social networking services centred around our genomes.

• Once we have our personal genomic information, what will we do with it and how might this information be used outside the medical context?
• How will physicians educate patients about the significance of genetic risk information?
• Will already-strained health-care systems be able to cope with the inevitable influx of “worried well” patients seeking follow-up investigations for genetic risks that are not clinically meaningful?

Caulfield and his colleagues pose these questions and warn that the routine generation of individual genome sequences will pose challenges to our health-care system. They argue that only clinically meaningful genomic test results should be integrated into medical decision-making — however, this will require clear standards, multidisciplinary collaboration and careful consideration of the ethical, social and clinical implications. Drs. Amy L. McGuire of Baylor College of Medicine, Mildred K. Cho of Stanford University in Palo Alto, California; Sean E. McGuire of The University of Texas M.D. Anderson Cancer Center and Timothy Caulfield of the University of Alberta in Edmonton, Canada, participated in this study. ......... ZenMaster

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Gene Assigns ID Tags to Help Organize the Developing Brain

Gene Assigns ID Tags to Help Organize the Developing Brain September 21, 2007 The developing nervous system is a seemingly chaotic and exceedingly complex jumble of cells with specialized missions, unique architectures, and stereotyped patterns of neuronal connections, or synapses. How neurons' dendrites and axons weave themselves into precise neural circuits during development remains a challenging question in neurobiology. What are the molecular tags on the surface of neurons that allow them to distinguish between each other? A single gene capable of producing more than 38,000 cell surface proteins is an essential tool in assuring the assembly of precise neural circuits in the fruit fly, Drosophila melanogaster. Now, two teams of researchers from the Howard Hughes Medical Institute (HHMI) have demonstrated how these closely related proteins establish the specificity that allows them to serve as identification tags for individual neurons. ......... ZenMaster

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Promising new source of stem cells

Stem cells derived from adult testes produce wide range of tissue types Wednesday, 19 September 2007 After a decade of research, Howard Hughes Medical Institute scientists have succeeded in reprogramming adult stem cells from the testes of male mice into functional blood vessels and contractile cardiac tissue. The research offers a promising new source of stem cells for use in organ regeneration studies. Some scientists think that organ-specific adult stem cells may offer the same therapeutic potential as embryonic stem cells, without the ethical concerns or the risk of immune rejection that are associated with embryonic stem cell therapies. However, adult stem cells may lack the plasticity and pluripotency of embryonic stem cells’ capacity to generate any cell type. The study of adult stem cells has also been limited by their relative scarcity in various organs and the attendant difficulties in identifying and harvesting them, as well as differentiating them in large quantities into functional vascularised tissues. HHMI investigator Shahin Rafii and his colleagues at Weill Cornell Medical College appear to have solved some of these problems in male mice. Using spermatogonial progenitor cells obtained from the mouse’s testes, the researchers reprogrammed the cells to form multipotent adult spermatogonial-derived stem cells. If the same can be done with human cells, they say, adult stem cells may be a promising source of new therapies for men, for diseases such as vascular diseases, heart disease, Alzheimer’s, Parkinson’s, stroke, diabetes, and even cancer. Scientists have had good success in deriving pluripotent stem cell lines — those with the ability to develop into multiple cell types — from adult testes cells. But only a small subset of cells from the testes has the potential to become pluripotent, and until now, investigators have lacked a means to identify and isolate them. In a paper published online in the September 20, 2007, issue of the journal Nature, Rafii and colleagues at Weill Cornell Medical College and Memorial Sloan-Kettering Cancer Center report that they have identified a novel cell surface marker that is expressed on a unique set of cells within adult testes known as the spermatogonial stem and progenitor cells (SPCs). The marker, GPR125, enabled the scientists to identify and harvest a large number of SPCs from adult mouse testes, then propagate and reprogram them in the lab to become stem cells that could differentiate into many cell types. The researchers demonstrated that these multipotent adult spermatogonial-derived stem cells (MASCs) could develop in vivo into working blood vessel (endothelial) cells and tissue, as well as contractile cardiac tissue, brain cells, and a host of other cell types. They also injected MASCs from culture into mouse blastocysts — embryonic cells — that they implanted in mature female mice. When the blastocysts developed into mice, the researchers could see that the MASCs had differentiated into many kinds of tissue. These data suggested that the MASCs are truly multipotent: reprogrammable to differentiate into functional tissues. Ten years ago, Rafii observed that human testicular cancer cells share many characteristics with adult stem cells. As an oncologist, he also noticed that a large number of patients with testicular cancer develop tumours called teratomas, which contain different types of tissue. Based on these observations, he reasoned that spermatogonia, whose sole function is to generate the precursors to sperm, have the potential to readily give rise to pluripotent cells. As such, he thought, they might prove more amenable to reprogramming than other adult stem cells. Using gene screening studies, Rafii and colleagues discovered a potential specific surface marker on SPCs. Comparison of all cells in the adult testis showed that this G-protein coupled receptor, known as GPR125, was expressed on SPCs, but not other mature germ cells. With GPR125 in hand, Rafii could isolate large numbers of SPCs from adult mouse testes. They also established a highly sophisticated culture system in which the progenitor cells rapidly grow and divide, creating a large population of cells that can be converted into MASCs. “It appears that these specialized GPR125-positive spermatogonial cells could be an easily obtained and manipulated source of stem cells with a similar capability to form new tissues that we see in embryonic stem cells,” said Rafii. For male patients, he believes, “It could someday mean a readily available source of stem cells that gets around ethical issues linked to embryonic stem cells. It also avoids issues linked to tissue transplant rejection, since these autologous cells come from the patient’s own body.” Rafii’s team is currently pursuing a similar study of human testes to determine whether stem cells derived from their spermatogonial progenitor cells share the pluripotency of the mouse MASCs. “We believe this to be an easily obtainable goal in the near future,” he said. If they succeed, several steps remain before such stem cells could be applicable to humans. “We still have to learn the exact biochemical and epigenetic ‘switch’ that tells GPR125-positive SPCs to convert into MASCs,” said Marco Seandel, a senior post-doctoral fellow in Rafii’s laboratory who is the first author of the Nature paper. “Discovering that switch will be crucial to our being able to create MASCs on demand.” There is a chance that implanted cells derived from MASCs may trigger cancer in the recipient. This is an area that requires further investigation, Rafii said. However, he noted, “So far, we haven’t seen any cancer or evidence of pro-cancerous activity in adult mice that are implanted with differentiated MASC cell tissue derivatives.” Rafii and his team have worked out the growing conditions that coax spermatogonial progenitor cells to develop into MASC germ lines — genetically stable stem cells that continue reproducing indefinitely. Stem cell studies have been limited to date by the scarcity of germ cell lines. “None of these GPR125-positive germ cell lines was previously readily available for genetic, biochemical, and cellular analysis by other laboratories,” says Rafii. “We intend to share them with other researchers.” Rafii’s lab is now investigating whether GPR125 can be used to isolate cells from other adult tissues that can be converted into multipotent stem cells. His group has also begun pursuing a similar effort in ovaries. “It’s much more difficult,” he said. “However, it is possible that reprogrammable stem cells with similar properties to GPR125-positive SPCs may also exist, although at very low numbers, in adult mouse or human ovaries.” His lab is actively investigating this intriguing possibility, Rafii said. ......... ZenMaster

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Stem cells in adult testes provide alternative to ESCs for organ regeneration

Isolation of specialized subsets of spermatogonial stem cells generate a wide range of cell and tissue types Wednesday, 19 September 2007 Easily accessed and plentiful, adult stem cells found in a male patient's testicles might someday be used to create a wide range of tissue types to help him fight disease — getting around the need for more controversial embryonic stem cells. That's the promise of a breakthrough study in mice led by a team from Weill Cornell Medical College in New York City, who report their findings in the September 20 issue of Nature. Using spermatogonial progenitor stem cells (SPCs) obtained from the mouse's testes, the researchers were able to redirect the cells' development in the lab to form so-called "multi-potent adult spermatogonial-derived stem cells" (MASCs). It was these cells that went on to develop into working blood vessel (endothelial) cells and tissue, as well as cardiac cells, brain cells and a host of other cell types. Prior research conducted elsewhere has used genetic manipulation to reprogram adult cells derived from connective tissue to acquire stem-cell potential, differentiating into various organ-specific tissues. However, this reprogramming method — called "induced pluripotency" — resulted in generation of multi-potent stem cells that carried an increased risk of transforming into malignant cells. "What's really novel about our work is that — unlike induced pluripotency — these mouse SPCs do not require any addition or tweaking of genes to get them to form the multi-potent cells (MASCs) that then go on to produce all of these cell types," notes senior author Dr. Shahin Rafii, Arthur Belfer Professor of Genetic Medicine and director of the Ansary Stem Cell Center for Regenerative Medicine at Weill Cornell Medical College and a noted Howard Hughes Medical Institute investigator. "Some hurdles remain, of course — we have to replicate these findings in humans, and we haven't discovered the exact 'switch' that would allow us to control SPC development on demand," Dr. Rafii says. "Nevertheless, it appears that these unique specialized spermatogonial cells could be an easily obtained and manipulated source of stem cells with exactly the same capability to form new tissues that we see in embryonic stem cells." SPCs lie within a specific area of the testes and their sole function is to generate the precursors to sperm. "Normally, the spermatogonial progenitor cell is committed to only that function, and they're remarkably efficient, keeping men fertile well into advanced age," notes the study's lead author, Dr. Marco Seandel, researcher at the Howard Hughes Medical Institute and researcher/medical oncology fellow at Memorial Sloan-Kettering Cancer Center in New York City. Dr. Seandel provided the first real breakthrough in this research, developing the first efficient means of growing large quantities of SPCs for experimental use in the lab. "That really allowed us to go full steam ahead in examining the potential of these very interesting cells," explains Dr. Rafii. In their experiments, the Weill Cornell team concocted the perfect in vitro biochemical environment for the SPCs. This included particular helper cell types and growth factors aimed at fostering SPCs development away from creating germ cells and towards what scientists called "multipotency" — the ability to develop into many different cell types. Along the way, the team also cleared another hurdle. "One problem with working with SPCs is that they've been extremely difficult to identify. We discovered that, within the testicular environment, only SPCs express a particular marker called GPR125," Dr. Seandel says. "That's a quantum leap forward in terms of being able to harvest and work with these cells." Left to "soak" in their specially designed cell culture conditions, SPCs eventually made the change the team was hoping for. They did not develop into germ cells but instead grew to become multi-potent adult spermatogonial-derived stem cells (MASCs). In both in vitro and mouse-tissue studies, the Weill Cornell group watched as the MASCs differentiated into the full range of cell types. "We took them furthest when it came to endothelial cells," says Dr. Daylon James, a co-author and investigator in Dr. Rafii's laboratory. "In experiments in live mouse tissue, we were able to show that these MASC-derived endothelial cells did more than just form — they also joined up with, and functioned alongside, other blood vessels." MASCs also produced contractile "beating heart" cardiac cells, neurons, and muscle cells in the laboratory, the researchers add. But challenges remain. "We still don't understand the exact biochemical and genetic 'switch' that tells the cells to become MASCs," Dr. Seandel says. "Discovering that switch will be crucial to our being able to create MASCs on a routine basis." "The other hurdle is to repeat this success in human cells, by utilizing the same stem-cell markers, including GPR125 and also another specific marker, Plzf," states Dr. Pier Paolo Pandolfi, a collaborator in the study. Dr. Pandolfi is currently a professor at Harvard Medical School. Drs. Ilaria Falciatori, Sergey Shmelkov and Jiyeon Kim are other researchers in Dr. Rafii's lab, who are using GPR125 to isolate stem cells from other adult tissues with the potential of converting them into multi-potent stem cells with regenerative potential. Still, the findings in Nature are extremely promising. "For male patients, it could someday mean a readily available source of stem cells that gets around ethical issues linked to embryonic stem cells. It also avoids issues linked to tissue transplant rejection, since these 'autologous stem cells' are derived from the patient's own body," Dr. Rafii says. Given the pioneering surgical technology developed by the Department of Urology at Weill Cornell — by Drs. Peter Schlegel, Marc Goldstein and Douglas Scherr — it is expected that routine retrieval of adult human testicular tissue could be performed safely and in a timely fashion. Would such an approach work in the female ovary, which also contains a large population of germ cells? The Weill Cornell team says similar techniques might work there as well, although at this point it's just a theory. "Our achievement using these testes-derived cells has taken us over a decade of painstaking investigation to achieve," says Dr. Rafii. "It points to the potential of this remarkable, but — until now — poorly accessed and understood stem cell." "We hope this seminal paper will set the stage for designing clinical strategies for regenerating failing organs in patients with heart disease, Alzheimer's, Parkinson's, stroke, diabetes, arthritis, macular degeneration and infertility induced by chemotherapy and irradiation," Dr. Rafii adds. "Delivering stem cells derived from MASCs, loaded with toxic factors, to the tumour microenvironment may also provide a novel strategy to target tumour blood vessels and inhibit cancer growth and metastasis." Reference: Generation of functional multipotent adult stem cells from GPR125+ germline progenitors Marco Seandel1, Daylon James, Sergey V. Shmelkov, Ilaria Falciatori, Jiyeon Kim, Sai Chavala, Douglas S. Scherr, Fan Zhang, Richard Torres, Nicholas W. Gale, George D. Yancopoulos, Andrew Murphy, David M. Valenzuela, Robin M. Hobbs, Pier Paolo Pandolfi & Shahin Rafii Nature 449, 346-350 (20 September 2007) doi:10.1038/nature06129 ......... ZenMaster

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Importance of Gene Regulation For Common Human Disease

Genes and disease? It's what you do with what you have that counts Monday, 17 September 2007 A new study published in Nature Genetics on Sunday 16 September 2007 show that common, complex diseases are more likely to be due to genetic variation in regions that control activity of genes, rather than in the regions that specify the protein code. This surprising result comes from a study at the Wellcome Trust Sanger Institute of the activity of almost 14,000 genes in 270 DNA samples collected for the HapMap Project. The authors looked at 2.2 million DNA sequence variants (SNPs) to determine which affected gene activity. They found that activity of more than 1300 genes was affected by DNA sequence changes in regions predicted to be involved in regulating gene activity, which often lie close to, but outside, the protein-coding regions. "We predict that variants in regulatory regions make a greater contribution to complex disease than do variants that affect protein sequence," explained Dr Manolis Dermitzakis, senior author from the Wellcome Trust Sanger Institute. "This is the first study on this scale and these results are confirming our intuition about the nature of natural variation in complex traits.” "One of the challenges of large-scale studies that link a DNA variant to a disease is to determine how the variant causes the disease: our analysis will help to develop that understanding, a vital step on the path from genetics to improvements in healthcare." Past studies of rare, monogenic disease, such as cystic fibrosis and sickle-cell anaemia, have focused on changes to the protein-coding regions of genes because they have been visible to the tools of human genetics. With the HapMap and large-scale research methods, researchers can inspect the role of regions that regulate activity of many thousands of genes. The HapMap Project established cell cultures from participants from four populations as well as, for some samples, information from families, which can help to understand inheritance of genetic variation. The team used these resources to study gene activity in the cell cultures and tie that to DNA sequence variation “We have generated an information resource readily available to investigators working in the mapping of variants underlying complex traits. Regions of association can be correlated with signatures of regulatory regions affecting gene expression” explained Dr Panos Deloukas, Senior Investigator at the Wellcome Trust Sanger Institute “We found strong evidence that SNP variation close to genes — where most regulatory regions lie — could have a dramatic effect on gene activity,” said Dr Barbara Stranger, post-doctoral fellow at WT Sanger Institute. "Although many effects were shared among all four HapMap populations, we have also shown that a significant number were restricted to one population." They also showed that genes required for the basic functions of the cell — so-called housekeeping genes — were less likely to be subject to genetic variation. "This was exactly as we would expect: you can't mess too much with the fundamental life processes and we predicted we would find reduced effects on these genes," said Dr Dermitzakis. The study also detected SNP variants that affect the activity of genes located a great distance away. Genetic regulation in the human genome is complex and highly variable: a tool to detect such distant effects will expand the search for causative variants. The authors note, however, that the small sample size of 270 HapMap individuals is sensitive enough to detect only the strongest effects. The results of this study are becoming available in public databases such as Ensembl for researchers to use. The paper is accompanied by two others examining effects of changes to regulatory DNA in samples from asthma and from heart study patients. Reference: Population genomics of human gene expression. Barbara E Stranger, Alexandra C Nica, Matthew S Forrest, Antigone Dimas, Christine P Bird, Claude Beazley, Catherine E Ingle, Mark Dunning, Paul Flicek, Daphne Koller, Stephen Montgomery, Simon Tavaré, Panos Deloukas & Emmanouil T Dermitzakis Nature Genetics advance online publication, 16 September, 2007 ......... ZenMaster

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Alan Trounson named California's new stem cell chief

Alan Trounson named California's new stem cell chief Saturday, 15 September 2007 The California Institute of Regenerative Medicine (CIRM), based in San Francisco, has been searching for a science chief since its first president, Zach Hall, retired at the end of April. On Friday, the California's stem cell agency named the Australian stem cell scientist Alan Trounson as its new president. Twenty members of the 29-person committee that oversees the agency were in attendance at Friday's monthly meeting in Los Angeles. All 20 voted for Trounson's appointment, instantly propelling him to the forefront of stem cell research. Trounson, 61, said he is ready to start a new scientific chapter to a career spent in the laboratory. "It's just a wonderful conclusion to a career in science," said Trounson. "These things don't happen often to us colonials down under." Trounson earned undergraduate degrees from the University of New South Wales in Sydney and his doctorate in embryology from Sydney University in 1974. He is currently director of Monash University's stem cell program in Melbourne. Trounson founded the Australia's Stem Cell Center in 2003, and is well known globally for his work in stem cell and human fertilization. He has also launched eight biotechnology companies, including Singapore-based Embryonic Stem Cell International. Trounson said he is no longer an investor in that company, or any other, working with human embryonic stem cells. Trounson will oversee a staff of about 30 and help the agency meet its goals laid out in a 150-page plan Hall helped draft before he departed. The most ambitious goal of the plan is to move the research out of the laboratory and into tests on people within 10 years. ......... ZenMaster

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International ethical guidelines for biobanks

International ethical guidelines for biobanks Friday, 14 September 2007 Many sets of guidelines and regulations, and great differences among countries, is what medical researchers encounter if they want to use previously collected samples from biobanks in their research. For one thing, this makes it extremely complicated to carry out major international studies. In the latest issue of Nature Biotechnology, Swedish ethics researchers at the Center for Bioethics (CBE), together with leading biobank researchers, put forward a pioneering solution: a set of practical ethical guidelines for biobank research. Biobanks consist of systematically gathered biological samples and are valuable for both research and medical treatments. When tissues samples are linked to good clinical data, they become indispensable to medical science. At the same time a number of ethical issues are raised regarding the use of these samples. For instance, can we be certain that information about an individual will not reach the wrong people, such as employers and insurance companies. “It is crucial to be able to weigh the conflicting interests, so that the regulation of biobank research doesn’t become a patient security problem in diagnosis, care, and treatment,” says Mats G. Hansson, professor of biomedical ethics and director of the Center for Bioethics at the Karolinska Institute and Uppsala University in Sweden. Today there is a plethora of extremely comprehensive guidelines and regulations in different countries, which entails major complications for biobank scientists, especially in international collaborative projects. In other words, there is a crying need for a simple model providing a comprehensive ethical balancing of medical needs and personal integrity concerns. The article in Nature Biotechnology presents for the first time an ethical framework for research using previously collected tissue samples, guidelines that can be used as a practical and direct instrument for researchers. Together with an article by the same researchers in the journal The Lancet Oncology from 2006, which provides guidance for the collection of new samples, and an article by Mats G. Hansson published in the latest issue of Pathobiology presenting a manual for biobank research, central issues involving biobank research have now been given a comprehensive solution. Hansson feels that it is important that ethical questions surrounding medical research be discussed and examined in the same forum as the scientific discussion is carried on. “It’s also important that proposals regarding the ethical balancing of various interests be put through the same type of independent scrutiny by being peer-reviewed in established scientific journals, just like medical research,” he states. “The framework is not only an instrument for researchers, but can also serve as a guide for ethics committees throughout Europe.” Ref: Ethical framework for previously collected biobank samples Gert Helgesson, Joakim Dillner, Joyce Carlson, Claus R Bartram & Mats G Hansson Nature Biotechnology, doi:10.1038/nbt0907-973b ......... ZenMaster

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Human Embryonic Stem Cells Used To Grow Cartilage

Rice University method is first to yield cartilage-like cells, engineer human cartilage Thursday, 06 September 2007 Rice University biomedical engineers have developed a new technique for growing cartilage from human embryonic stem cells, a method that could be used to grow replacement cartilage for the surgical repair of knee, jaw, hip, and other joints. "Because native cartilage is unable to heal itself, researchers have long looked for ways to grow replacement cartilage in the lab that could be used to surgically repair injuries," said lead researcher Kyriacos A. Athanasiou, the Karl F. Hasselmann Professor of Bioengineering. "This research offers a novel approach for producing cartilage-like cells from embryonic stem cells, and it also presents the first method to use such cells to engineer cartilage tissue with significant functional properties." Using a series of stimuli, the researchers developed a method of converting the stem cells into cartilage cells. Building upon this work, the researchers then developed a process for using the cartilage cells to make cartilage tissue. The results show that cartilages can be generated that mimic the different types of cartilage found in the human body, such as hyaline articular cartilage — the type of cartilage found in all joints — and fibrocartilage — a type found in the knee meniscus and the jaw joint. Athanasiou said the results are exciting, as they suggest that similar methods may be used to convert the stem cell-derived cartilage cells into robust cartilage sections that can be of clinical usefulness. Athanasiou's group has been one of the most successful in the world at studying cartilage cells and, especially, engineering cartilage tissues. He said that for his research the primary advantage that embryonic stem cells have over adult stem cells is their ability to remain malleable. "Identifying a readily available cell source has been a major obstacle in cartilage engineering," Athanasiou said. "We know how to convert adult stem cells into cartilage-like cells. The more problematic issue comes in trying to maintain a ready stock of adult stem cells to work with. These cells have a strong tendency to convert from stem cells into a more specific type of cell, so the clock is always ticking when we work with them." By contrast, Athanasiou said his research group has found it easier to grow and maintain a stock of embryonic stem cells. Nonetheless, he is quick to point out that there is no clear choice about which type of stem cell works best for cartilage engineering. "We don't know the answer to that," Athanasiou said. "It's extremely important that we study all potential cell candidates, and then compare and contrast those studies to find out which works best and under what conditions. Keep in mind that these processes are very complicated, so it may well be that different types of cells work best in different situations." The results are available online and scheduled to appear in the September issue of the journal Stem Cells. The study involved cells from an NIH-sanctioned stem cell line. ......... ZenMaster

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UK Government Approves Hybrid Embryo Creation

UK Government Approves Hybrid Embryo Creation Thursday, 06 September 2007 The UK government's fertility regulator HFEA yesterday agreed to allow scientists to create human-animal hybrid embryos for stem cell isolation and medical research into debilitating diseases. Dr Lyle Armstrong of Newcastle University's Institute for Human Genetics, who is one of the applicants for this new research, called the decision “excellent news”. "It is a positive outcome, not just for our work but for the progress of British science in general, and we hope that this will lead to new technologies to benefit everyone,” he said. “It does seem a little abhorrent at first analysis, but you have to understand we are using very, very little information from the cow in order to do this reprogramming idea.” “It's not our intention to create any bizarre cow-human hybrid; we want to use those cells to understand how to make human stem cells better.” Another team from King’s College in London has also applied to the HFEA to use hybrid embryos. Dr Stephen Minger, of King's College, said he “applauded” the HFEA for its decision as it was the only ethically justifiable option if scientists were to push forward with their research. It is now expected individual hearings for these two applications will be held in November with other scientists expected to follow suit. HFEA statement on its decision regarding hybrid embryos 5 September 2007 “The decision on how the HFEA should approach the licensing of human-animal hybrids and chimera research has presented a particular challenge as this research is so novel in legal, scientific and ethical terms.” ”In order to ensure that the Authority was able to make an appropriate and reasoned decision, we needed to ensure we had a comprehensive and robust evidence base as a foundation for that decision.” ”Once we had established that such research would legally fall within the HFEA's remit to license, we were then able to start to assess whether such research would, in principle, be necessary and desirable in both scientific and ethical terms. ” ”As such the HFEA, working with support from the Government's Sciencewise programme, put together a detailed and comprehensive consultation gathering evidence from scientists and the wider public about the issues raised by this research. This has been far more than just opinion polling and has involved a series of detailed deliberative sessions where the full range of issues raised by such research were discussed. This enabled participants to make their own informed judgements, asking questions and challenging their own views. ”Having looked at all the evidence the Authority has decided that there is no fundamental reason to prevent cytoplasmic hybrid research. However, public opinion is very finely divided with people generally opposed to this research unless it is tightly regulated and it is likely to lead to scientific or medical advancements. ” ”This is not a total green light for cytoplasmic hybrid research, but recognition that this area of research can, with caution and careful scrutiny, be permitted. Individual research teams should be able to undertake research projects involving the creation of cytoplasmic hybrid embryos if they can demonstrate, to the satisfaction of an HFEA licence committee, that their planned research project is both necessary and desirable. They must also meet the overall standards required by the HFEA for any embryo research. ” ”Having looked at the principles behind this kind of research, an HFEA licence committee will now look at the details of the two specific research applications that were submitted earlier this year. We would hope to have a decision on both applications in November. ” ”In general, people who do not fundamentally oppose embryo research are prepared to accept that human animal research may have some value. But there is a clear demand from people to know more about what researchers are doing and their plans for future work, highlighting a need for better communication about science and research from both the scientific community and ourselves as regulator. In the coming months we will be looking to see how this can be delivered. ” ”In terms of other kinds of hybrid and chimera research, it became very clear that not only did the scientific community not wish to perform such research at present but that the prospect was so distant that they could not envisage what form this research would possibly take in the future. ” ”The Authority felt it would be completely wrong to make a decision on broader hybrid and chimera research without an adequate evidence base. However, the HFEA will continue to monitor the potential for this wider research and any emerging evidence through its 'horizon scanning’ programme.” Links: HFEA ......... ZenMaster

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UK HFEA watchdog should approve 'cybrid' embryos

UK HFEA Watchdog should approve 'cybrid' embryos Tuesday, 04 September 2007 The creation of embryos that are part-human and part-animal should be approved by the Government’s fertility watchdog on Wednesday, after a consultation revealed strong scientific support for the work and only limited public concern. The Human Fertilisation and Embryology Authority (HFEA) is expected to agree in principle that scientists can use interspecies embryos that are 99.9 per cent genetically human to investigate diseases such as Parkinson’s and diabetes. A decision to allow cytoplasmic hybrid or “cybrid” embryos, formed by placing human DNA into an empty animal egg, is anticipated after the four-month consultation found that most opposition to the experiments comes from people who object to all embryo research. The wider public, by contrast, was broadly supportive: a poll found that 61 per cent agreed with such work if it might improve understanding of diseases. Scientists also backed the research overwhelmingly. A positive ruling would clear the way for the authority to consider licence applications from research teams at King’s College, London and the University of Newcastle-upon-Tyne, who want to produce cybrids to create stem cell models of disease. See also: UK Government Approves Hybrid Embryo Research ......... ZenMaster

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First individual genome sequence published

First individual genome sequence published Tuesday, 04 September 2007 Independent sequence and assembly of the six billion base pairs from the genome of one person ushers in the era of individualized genomics Researchers at the J. Craig Venter Institute (JCVI), along with collaborators at The Hospital for Sick Children in Toronto and the University of California San Diego (UCSD), have published a genome sequence of an individual, Craig Venter, that covers both sets of chromosomes that were inherited from each parent. Two other versions of the human genome currently exist — one published in 2001 by J. Craig Venter, Ph.D., and colleagues at Celera Genomics, and another at the same time by a consortium of government-funded researchers. These genomes were not of any single individual, but, rather, were a melding of DNA from various people. In the case of Celera, it was a consensus assembly from five individuals, while the government-funded version was a haploid genome based on sequencing from a limited number of individuals. Both versions greatly underestimated human genetic diversity. This new genome, known as the “HuRef” version, represents the first time a true diploid genome from one individual — Dr. Venter — has been published. The research is available in the latest issue of the open-access journal PLoS Biology. Researchers at the JCVI have been sequencing and analyzing this version of Dr. Venter’s genome since 2003. Building on reanalyzed data from Dr. Venter’s genome that constituted 60% of the previously published Celera genome, the team had the goal of constructing a true reference human genome based on one individual. Using whole genome shotgun sequencing and highly accurate long reads from Sanger dideoxy automated DNA sequencing, the team produced additional data making the final 32 million sequences. From the combined data set of more than 20 billion base pairs, the researchers were able to assemble the human genome with an overall length of 2.810 billion base pairs. The genome was covered 7.5 times, ensuring that each set of contributing chromosomes was covered over 3.2 times for greater than 96% coverage of the two parental genomes. The team at JCVI compared and contrasted the new HuRef diploid genome sequence to earlier versions of published human genomes and found that the HuRef version improved upon both these early versions by providing more and correctly oriented base pairs. Since the HuRef genome is diploid, each of the parental chromosomes could be directly compared to each other. One of the most surprising and important findings from this research was the high degree of genetic variation that was found between two chromosomes within a single individual. “Each time we peer into the human genome, we uncover more valuable insight into our intricate biology,” said Dr. Venter. “With this publication, we have shown that human-to-human variation is more than seven-fold greater than earlier estimates, proving that we are in fact very unique individuals at the genetic level.” He added, “It is clear, however, that we are still at the earliest stages of discovery about ourselves, and only with continued sequencing of more individual genomes will we be able to garner a full understanding of how our genes influence our lives.” Within the human genome, there are different kinds of DNA variants. The most studied type is single nucleotide polymorphisms, or SNPs. These have long been thought to be the most prevalent and perhaps the most important type of variant implicated in human traits and disease susceptibility. However, in this analysis of Dr. Venter’s genome, the team found a surprising number of other important variants. A total of 4.1 million variants covering 12.3 million base pairs of DNA were uncovered with more than 1.2 million new variants discovered. Of the 4.1 million variations between chromosome sets, 3.2 million were SNPs, while nearly one million were other kinds of variants, such as insertion/deletions (“indels”), copy number variants, block substitutions, and segmental duplications. While the SNPs outnumbered the non-SNP types of variants, the non-SNP variants involved a larger portion of the genome. This suggests that human-to-human variation is much greater than previously thought. The researchers suggest that much more research needs to be done on these non-SNP variants to better understand their role in individual genomics. According to Sam Levy, Ph.D., lead author and senior scientist at JCVI: “The ability to use unbiased, high throughput sequencing methods, coupled with advance computational analytic methods, enables us to characterize more comprehensively the wide variety of individual genetic variation. This offers us an unprecedented opportunity to study the prevalence and impact of these DNA variants on traits and diseases in human populations.” Another important feature that is made possible by having an individual, diploid genome is the ability to begin to do better and more informed haplotype assemblies. Haplotypes are groups of linked variants. Through the government-sponsored HapMap project, many common haplotypes have been identified; however, these are based on averages of large ethnogeographic populations rather than individuals. Having individual haplotypes would enable researchers to understand and find more rare or individual variants that would explain and help predict diseases in that particular person — a truly personalized, individualized genomics paradigm. In the HuRef analysis, the team used the 4.1 million variant set and new algorithms to build haplotype assemblies that, when compared to the HapMap project, represented longer and more complete linkages. The JCVI researchers expect this number to improve significantly as additional sequence coverage is added to HuRef using a variety of new sequencing technologies. Long-range haplotype linkages will enable much more complete analysis of human variation and the genetic association with complex human traits, behaviours’, and diseases. In the near future, the scientists believe that it will be possible to know from which parent various traits were inherited. Already in this analysis, the JCVI team has found more than 300 disease genes and 4,000 genes overall that exhibit different protein forms. This will be an important area for further study and analysis to determine how these altered proteins affect Dr. Venter’s health status. Reference: Levy S, Sutton G, Ng PC, Feuk L, Halpern AL, et al. (2007) The diploid genome sequence of an individual human. PLoS Biol 5(10): e254. doi:10.1371/journal.pbio.0050254. ......... ZenMaster

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