CellNEWS: December 2008

Tuesday, 30 December 2008

Genes That Made 1918 Flu Lethal Isolated

Genes That Made 1918 Flu Lethal Isolated
Tuesday, 30 December 2008

By mixing and matching a contemporary flu virus with the "Spanish flu" — a virus that killed between 20 and 50 million people 90 years ago in history's most devastating outbreak of infectious disease — researchers have identified a set of three genes that helped underpin the extraordinary virulence of the 1918 virus.

Writing today (Dec. 29) in the Proceedings of the National Academy of Sciences, a team led by University of Wisconsin-Madison virologists Yoshihiro Kawaoka and Tokiko Watanabe identifies genes that gave the 1918 virus the capacity to reproduce in lung tissue, a hallmark of the pathogen that claimed more lives than all the battles of World War I combined.

"Conventional flu viruses replicate mainly in the upper respiratory tract: the mouth, nose and throat. The 1918 virus replicates in the upper respiratory tract, but also in the lungs," causing primary pneumonia among its victims, says Kawaoka, an internationally recognized expert on influenza and a professor of pathobiological sciences in the UW-Madison School of Veterinary Medicine.

"We wanted to know why the 1918 flu caused severe pneumonia."

Autopsies of 1918 flu victims often revealed fluid-filled lungs severely damaged by massive haemorrhaging. Scientists assumed that the ability of the virus to take over the lungs is associated with the pathogen's high level of virulence, but the genes that conferred that ability were unknown.

Discovery of the complex and its role in orchestrating infection in the lungs is important because it could provide a way to quickly identify the potential virulence factors in new pandemic strains of influenza, Kawaoka says. The complex could also become a target for a new class of antiviral drugs, which is urgently needed, as vaccines are unlikely to be produced fast enough at the outset of a pandemic to blunt its spread.

To find the gene or genes that enabled the virus to invade the lungs, Kawaoka and his group blended genetic elements from the 1918 flu virus with those of a currently circulating avian influenza virus and tested the variants on ferrets, an animal that mimics human flu infection.

Substituting single genes from the 1918 virus onto the template of a much more benign contemporary virus yielded, for the most part, agents that could only replicate in the upper respiratory tract. One exception, however, included a complex of three genes that, acting in concert with another key gene, allowed the virus to efficiently colonize lung cells and make RNA polymerase, a protein necessary for the virus to reproduce.

"The RNA polymerase is used to make new copies of the virus," Kawaoka explains. Without the protein, the virus is unable to make new virus particles and spread infection to nearby cells.

In the late 1990s, scientists were able to recover genes from the 1918 virus by looking in the preserved lung tissue of some of the pandemic's victims. Using the relic genes, Kawaoka's group was able to generate viruses that carry different combinations of the 1918 virus and modern seasonal influenza virus.

When tested, most of the hybrid viruses only infected the nasal passages of ferrets and did not cause pneumonia. However, one did infect the lungs, and it carried the RNA polymerase genes from the 1918 virus that allowed the virus to make the key step of synthesizing its proteins.

In 2004, Kawaoka and his team identified another key gene from the 1918 virus that enhanced the pathogen's virulence in mice. That gene makes haemagglutinin, a protein found on the surface of the virus and that confers on viral particles the ability to attach to host cells.

"Here, I think we are talking about another mechanism," Kawaoka says.

“The RNA polymerase is used to make copies of the virus once it has entered a host cell. The role of haemagglutinin is to help the virus gain access to cells.”

Reference:
Viral RNA polymerase complex promotes optimal growth of 1918 virus in the lower respiratory tract of ferrets
Tokiko Watanabe, Shinji Watanabe, Kyoko Shinya, Jin Hyun Kim, Masato Hatta, and Yoshihiro Kawaoka
PNAS, December 29, 2008, doi: 10.1073/pnas.0806959106
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ZenMaster

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Thursday, 25 December 2008

First Embryonic Stem Cells Derived from Rats II

Recipe for capturing authentic embryonic stem cells may apply to any mammal
Thursday, 25 December 2008

Researchers have what they think may be a basic recipe for capturing and maintaining indefinitely the most fundamental of embryonic stem cells from essentially any mammal, including cows, pigs and even humans. Two new studies reported in the December 26th issue of the journal Cell, a Cell Press publication, show that a cocktail first demonstrated to work in mice earlier this year, which includes inhibitory chemicals, also can be used to successfully isolate embryonic stem cells from rats.

Authentic rat embryonic stem cells had never before been established.

The new discovery made in labs at both the University of Edinburgh and theUniversity of Southern California (USC), Los Angeles, is a major breakthrough for biomedical research, said Qi-Long Ying, an author on both studies who was at the University of Edinburgh and is now at USC. That's because it will allow researchers to readily produce genetically altered strains of rats, with conditions that mimic human disease, in a very targeted way. Austin Smith led the team at the University of Edinburgh and Ying led the USC team.

Humans and rats are physiologically more similar than humans and mice, making the study of rats more directly applicable to people, and rats' larger size also makes them easier to work with in many cases, according to the researchers. Humans and rats also tend to have similar responses to drugs.

The findings lend support to the notion that embryonic stem cells will remain in their undifferentiated, pluripotent state when they are shielded from particular outside signals. (Pluripotent refers to the ability to differentiate into any cell or tissue type). Scientists had previously thought that the maintenance of stem cells depended on activating signals from outside, including growth factors and other chemicals.

Embryonic stem cells are derived from the inner cell mass of blastocysts. Blastocysts are hollow balls of cells that form in early development. The inner cell mass is a cluster of cells inside the blastocyst that goes on to form the embryo.

Authentic embryonic stem cells are defined by three cardinal properties: unlimited symmetrical self-renewal in the lab; comprehensive contribution to primary chimeras; and generation of functional egg and sperm for genome transmission. Chimeras are produced when embryonic stem cells are inserted into a developing blastocyst and those stem cells go on to contribute to a normal embryo with cells of two origins, Ying explained. Because those embryonic stem cells can contribute to the germ line, any genetic alterations they carry – such as the loss or gain of a gene – can be passed on to the next generation.

The versatility of embryonic stem cells, combined with the ease with which they can be manipulated genetically, has provided a powerful means to elucidate gene function and create disease models via the generation of transgenic, chimeric, and knock-out animals. Although embryonic stem cells have been routinely derived from particular strains of mice since 1981, their capture from rats or other animals had remained elusive.

While human embryonic stem cell lines do exist, Ying said, it's not clear that they represent the most grounded stem cell state because the essential properties can't be demonstrated for obvious ethical reasons.

Now, Ying and Smith's teams show that a two- or three-ingredient concoction known as 2i or 3i respectively, which inhibits signals that would otherwise activate the differentiation process, maintains rat embryonic stem cells in their natural default state, allowing them to self-renew, or multiply, as generic stem cells. (The cocktails include inhibitors of GSK3, MEK, and FGF receptor tyrosine kinases.)

Most importantly, the isolated cells can produce high rates of chimerism when reintroduced into early stage embryos and can transmit through the germline, they report.

"In the past two decades, embryonic stem cells have been routinely used to create loss of function (knock-out) or gene replacement (knock-in) mutations by homologous recombination in the mouse, providing an invaluable tool for the functional characterization of genes," Ying's group wrote.

"Now, the availability of true rat embryonic stem cells provides an opportunity to adapt the technology developed in the mouse to the rat."

The new findings raise "the possibility that culture formulations based on the 3i/2i principle could facilitate derivation of embryonic stem cells from other mammals, including livestock species," Austin Smith's team wrote.

"It will also be of interest to investigate whether supernumerary human embryos cultured in 3i/2i may give rise to pluripotent cell lines that are qualitatively different from current human 'embryonic stem' cells" more like ground state rodent embryonic stem cells.

References:
Capture of Authentic Embryonic Stem Cells from Rat Blastocysts
Mia Buehr, Stephen Meek, Kate Blair, Jian Yang, Janice Ure, Jose Silva, Renee McLay, John Hall, Qi-Long Ying, Austin Smith
Cell, Volume 135, Issue 7, 1287-1298, doi:10.1016/j.cell.2008.12.007

Germline Competent Embryonic Stem Cells Derived from Rat Blastocysts
Ping Li, Chang Tong, Ruty Mehrian-Shai, Li Jia, Nancy Wu, Youzhen Yan, Eric N. Schulze, Houyan Song, Chih-Lin Shieh, Martin F. Pera, Qi-Long Ying
Cell, Volume 135, Issue 7, 1299-1310, doi:10.1016/j.cell.2008.12.006

First ESCs Derived from Rats I
CellNEWS - Thursday, 25 December 2008
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ZenMaster

For more on stem cells and cloning, go to CellNEWS at
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First Embryonic Stem Cells Derived from Rats I

Finding represents major breakthrough for biomedical research
Thursday, 25 December 2008

Researchers at the University of Southern California (USC) have, for the first time in history, derived authentic embryonic stem (ES) cells from rats. This breakthrough finding will enable scientists to create far more effective animal models for the study of a range of human diseases.

The research will be published in the Dec. 26 issue of the journal Cell.

"This is a major development in stem cell research because we know that rats are much more closely related to humans than mice in many aspects of biology. The research direction of many labs around the world will change because of the availability of rat ES cells," says Qi-Long Ying, Ph.D., assistant professor of Cell and Neurobiology at the Keck School of Medicine of USC, researcher at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, and the study's principal investigator.

The finding brings scientists much closer to creating "knockout" rats — animals that are genetically modified to lack one or more genes — for biomedical research. By observing what happens to animals when specific genes are removed, researchers can identify the function of the gene and whether it is linked to a specific disease.

"Without ES cells it is impossible to perform precise genetic modifications for the creation of the disease model we want," he says.

"The availability of rat ES cells will greatly facilitate the creation of rat models for the study of different human diseases, such as cancer, diabetes, high blood pressure, addiction and autoimmune diseases."

Ying, a native of China, notes that this breakthrough research occurred during 2008, the Chinese year of the rat.

Embryonic stem cells are derived from a group of cells called the inner cell mass in a very early stage embryo. ES cells provide researchers with a valuable tool to address fundamental biological questions, because they enable scientists to study how genes function, and to develop animals with conditions that mimic important human diseases.

Martin Evans of Cardiff University, UK, who was last year awarded the Nobel Prize in Medicine or Physiology, established the first ES cell lines from mice in 1981. Researchers have long been working on establishing rat ES cells, but faced technical hurdles because the conventional methods developed for the derivation of mouse cells did not work in rats.

Building on recent research into how ES cells are maintained, the USC researchers found that rat ES cells can be efficiently derived and grown in the presence of the "3i medium," which consists of molecules that inhibit three specific gene signalling components (GSK3, MEK and FGF receptor kinase). This approach insulates the stem cell from signals that would normally cause it to differentiate, or turn into specialized types of body cells. By blocking these signals, Ying and colleagues found that stem cells from rats, which have previously failed to propagate at all, could be grown indefinitely in the laboratory in the primitive embryonic state.

An accompanying study led by researchers at the University of Cambridge, UK, reported similar findings, independently verifying that authentic ES cells can be established from rats. Both papers will be published in the upcoming issue of Cell.

"The development of rat embryonic stem cells, long sought by researchers around the world, is a major advance in biomedical science," says Martin Pera, Ph.D., director of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC.

"These new stem cell lines will make a huge contribution to basic and applied research and drug development, by providing a technology platform for facile genetic manipulation of a mammalian species that is widely used in academic and industrial labs studying physiology, pathology and pharmacology."

Until now, authentic ES cells have never been established from humans or animals other than mice. This new key understanding into how ES cells are maintained in culture may eventually enable scientists to establish real ES cell lines from a number of other mammals, which could have significant implications for organ transplantations and the development of drug therapies, Ying says. Researchers at USC are currently working on generating the first gene knockout rat through ES cell-based technologies.

"If our work is feasible it is likely that many labs will follow up to generate different types of gene knockout rat models," he says.

"This will have a major impact on the future of biomedical research."

References:
Germline Competent Embryonic Stem Cells Derived from Rat Blastocysts
Ping Li, Chang Tong, Ruty Mehrian-Shai, Li Jia, Nancy Wu, Youzhen Yan, Eric N. Schulze, Houyan Song, Chih-Lin Shieh, Martin F. Pera, Qi-Long Ying
Cell, Volume 135, Issue 7, 1299-1310, doi:10.1016/j.cell.2008.12.006

Capture of Authentic Embryonic Stem Cells from Rat Blastocysts
Mia Buehr, Stephen Meek, Kate Blair, Jian Yang, Janice Ure, Jose Silva, Renee McLay, John Hall, Qi-Long Ying, Austin Smith
Cell, Volume 135, Issue 7, 1287-1298, doi:10.1016/j.cell.2008.12.007

First ESCs Derived from Rats II
CellNEWS - Thursday, 25 December 2008
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ZenMaster

For more on stem cells and cloning, go to CellNEWS at
http://cellnews-blog.blogspot.com/ and
http://www.geocities.com/giantfideli/index.html

Monday, 22 December 2008

Batten Disease Studied in Yeast Cells

Scientists express human gene mutations in yeast in order to study Batten disease, a fatal childhood neurodegenerative disorder
Monday, 22 December 2008

Scientists report that human gene mutations expressed in yeast cells can predict the severity of Batten Disease, a fatal nervous system disorder that begins during childhood. The new study published in Disease Models & Mechanisms (DMM), describes how the extent of changes in mutated cells paralleled the severity of symptoms seen in humans.

The initial, milder symptoms of Batten disease appear in children between ages 4 and 7. Children with this disorder (also known as juvenile neuronal ceroid lipfuscinosis, or JNCL) suffer vision loss and exhibit learning difficulties and behavioural changes. This is eventually followed by the appearance of seizures, and a devastating, progressive loss of mental and physical function, eventually leading to death before young adulthood.

Mutations in the gene CLN3 cause Batten Disease, but scientists do not fully understand the role of CLN3 in cell function. Thus, in order to learn more about this gene, researchers at the University College London created a variety of mutations based on CLN3 gene defects identified in Batten disease patients. They studied the effects of these mutations in a fission yeast protein highly similar to CLN3. The research team found that human mutations that caused a severe Batten disease progression likewise caused severe cell abnormalities in the yeast. Likewise, mutations found in mild cases of Batten disease resulted in less severe yeast cell changes.

Not only does this study help researchers understand the mechanism underlying Batten disease, but this yeast model can also be used to investigate therapeutic compounds to treat Batten disease and related illnesses.

The report was written by R.L. Haines, S. Codin, and S.E. Mole at the MRC Laboratory for Molecular Cell Biology at University College London. The report is published in the January/February issue of a new research journal, Disease Models & Mechanisms (DMM), published by The Company of Biologists, a non-profit based in Cambridge, UK.
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ZenMaster

For more on stem cells and cloning, go to CellNEWS at
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Patient-derived iPS Cells Retain Disease Traits

Patient-derived Induced Stem Cells Retain Disease Traits
Monday, 22 December 2008

When neurons started dying in Clive Svendsen's lab dishes, he couldn't have been more pleased.

The dying cells – the same type lost in patients with the devastating neurological disease spinal muscular atrophy – confirmed that the University of Wisconsin-Madison stem cell biologist had recreated the hallmarks of a genetic disorder in the lab, using stem cells derived from a patient. By allowing scientists the unparalleled opportunity to watch the course of a disease unfold in a lab dish, the work marks an enormous step forward in being able to study and develop new therapies for genetic diseases.

As reported this week in the journal Nature, Svendsen and colleagues at UW-Madison and the University of Missouri-Columbia created disease-specific stem cells by genetically reprogramming skin cells from a patient with spinal muscular atrophy, or SMA. In this inherited disease, the most common genetic cause of infant mortality, a mutation leads to the death of the nerves that control skeletal muscles, causing muscle weakness, paralysis, and ultimately death, usually by age two.

The nerves that control muscles, known as motor neurons (shown here in red), are lost in the devastating genetic disease called spinal muscular atrophy, causing weakness, paralysis, and early death. A team of UW-Madison stem cell biologists recreated the hallmarks of this disease in the lab using genetically reprogrammed stem cells created from a young SMA patient’s skin. The work gives scientists the opportunity to study the full progression of a disease in the lab and should improve understanding and treatment of genetic disorders. The motor neurons shown here were grown from cells from the patient’s healthy mother. Photo: provided by Clive Svendsen.

Genetic reprogramming of skin cells, first reported in late 2007 by UW-Madison stem cell biologists James Thomson and Junying Yu and a Japanese group led by Shinya Yamanaka, turns back the cells' developmental clock and returns them to an embryonic-like state from which they can become any of the body's 220 different cell types. The resulting induced pluripotent stem cells, known as iPS cells, harness the blank-slate developmental potential of embryonic stem cells without the embryo and have been heralded as a powerful potential way to study development and disease.

Just one year later, the new work is fulfilling that promise.

"When scientists study diseases in humans, they can normally only look at the tissues affected after death and then try to work out – how did that disease happen? It's a little like the police arriving at the scene of a road accident – the car's in the ditch, but they don't know how it got there or the cause of it," explains Svendsen, a professor of anatomy and neurology in the UW-Madison School of Medicine and Public Health and the Waisman Center, and co-director of the Stem Cell and Regenerative Medicine Center.

With iPS cells, he says, "Now you can replay the human disease over and over in the dish and ask what are the very early steps that began the process. It's an incredibly powerful new tool."

In the new study, the researchers created iPS cells from stored skin cells of a young SMA patient and his mother, who does not have the disease. The cells grew well in the lab, and the group developed a new method to efficiently drive them to make large numbers of motor neurons, the cells that control muscles and that are affected in SMA.

Initially, the motor neurons thrived in both samples. But after about a month, "the accident started happening," Svendsen says, and the motor neurons from the patient-derived cells began to disappear.

"The motor neurons we got started to die in culture, just like they do in the disease. This is the first validation of a human disease that we've modelled in a culture dish," he says.

They can now begin to dissect what kills the motor neurons and why these cells alone are targeted in the disease. Past studies to understand the effects of the SMA-causing mutation have often relied on the easy-to-obtain skin cells, which are not affected in SMA and offer limited insight into how and why motor neurons die, says UW-Madison researcher Allison Ebert, lead author on the new study.

"If we start to understand more of the mechanism of why the motor neurons specifically affected in the disease are dying, then potentially new therapies can be developed to intervene at particular times early in development," she explains. Current SMA treatment options are limited, and there is no cure.

Ebert points out that the patient-derived iPS cells can offer scientific advantages over other approaches, including embryonic stem cells, for studying disease. In effect, the researchers can watch the unfolding of an accident that has already occurred, and the known clinical outcome – the course and severity of the patient's disease – should help them understand how the changes they see in the cells fit into the bigger picture of the disease.

"The development of human-derived SMA motor neurons is an important step forward for the SMA field, especially as a variety of therapeutic avenues are being examined," agrees SMA expert Christian Lorson, a professor of veterinary pathobiology at MU and an author on the paper.

"To be able to investigate therapeutic activity in these cells, whether it be novel drugs, viral vectors, oligonucleotides, or a better understanding of disease pathology, the iPS SMA motor neurons represent an excellent disease-related context."

While complex and late-hitting disorders like Alzheimer's and Parkinson's diseases will be harder to model with iPS cells, the researchers say the approach should pave the way for studies of other genetic disorders, such as Huntington's disease.

"We have to find better ways to model complex human diseases that are difficult to reproduce in animals," Svendsen says.

"iPS cells represent a promising new research tool to reach this goal."

He credits the UW-Madison Stem Cell and Regenerative Medicine Center with facilitating the work, especially by drawing on the expertise of Yu and Thomson, who pioneered the technique, to create the iPS cells used in this study.

"This is an example of how the centre is working to collaborate on campus and off campus to bring these kinds of things to fruition," he says.

Reference:
Induced pluripotent stem cells from a spinal muscular atrophy patient
Allison D. Ebert, Junying Yu, Ferrill F. Rose, Jr, Virginia B. Mattis, Christian L. Lorson, James A. Thomson & Clive N. Svendsen
Nature advance online publication 21 December 2008, doi:10.1038/nature07677
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ZenMaster

For more on stem cells and cloning, go to CellNEWS at
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Thursday, 18 December 2008

Novel Types of Stem Cells Generated

Breakthrough may offer opportunity for expanding research, drug discovery
Thursday, 18 December 2008

The study, which appears in the December 18 online version of Cell Stem Cell and the January 2009 print edition of the journal, provides proof of principle that alternative sources of stem cells can be created.

The team, which included scientists from Scripps Research, Peking University, and the University of California, San Diego, conducted the studies to establish novel rat induced pluripotent stem cell lines (riPSCs) and human induced pluripotent stem cell lines (hiPSCs) by using a specific cocktail of chemicals combined with genetic reprogramming, a process whereby an adult cell is returned to its early embryonic state. Pluripotency refers to the ability of a cell to develop into each of the more than 200 cell types of the adult body.

Mimicking Human Physiology
Scientists genetically engineer embryonic stem cells to create mouse models that contain the engineered genes — so-called transgenic animals — in the hope of applying the knowledge gained from studying such mice to benefit humans. Although using mouse pluripotent embryonic stem cells has been the standard since these cells were first derived in 1981, researchers have long wanted to apply such powerful techniques to other animal species to help the study of human physiology and disease.

The major advantage of using other animal species, such as rats, is that the physiology of these animals can better mimic human physiology, for example, in studies of metabolic and neurological diseases. The size of other animals also is an advantage because larger organs and tissues are easier to work with. Because of these benefits, scientists have created transgenic animals from species other than mice, but the lack of pluripotent stem cells from these species and the tedious and imprecise techniques currently available has made the process difficult.

"Mouse models created with pluripotent embryonic stem cells are wonderful tools for understanding the fundamental biology of genes," says Sheng Ding, Ph.D., an associate professor in the Scripps Research Department of Chemistry who was senior author of the study with Peking University investigator Hongkui Deng, Ph.D.

"But in some important ways these models are less than ideal. Our demonstrated technologies will enable unprecedented and broad applications for better creating animal models from other species."

Novel and More Robust Human Pluripotent Stem Cells
In another closely related aspect of this work, Ding has also shown that a new kind of human pluripotent stem cell can now be created using the same chemical and reprogramming methods used to create the rat pluripotent stem cells. Human pluripotent stem cells hold promise for modelling human development and disease, testing drugs, and providing unlimited functional cells for cell replacement therapy.

"Recent studies have found, however, that conventional human embryonic stem cells represent a different pluripotent cell type and are not the counterpart of the conventional, and most useful, mouse embryonic stem cells," Ding says.

The issue is that pluripotent stem cells can be represented by cells from two distinct stages of embryonic development — the early pre-implantation blastocyst stage and the later post-implantation epiblast stage. Today, conventional mouse embryonic stem cells represent the pre-implantation stage pluripotent cells, and human embryonic stem cells appear to represent later post-implantation stage pluripotent cells.

Early- and late-stage cells have very different properties. For example, they respond differently to the same signals given to stem cells to differentiate into specific types of cells. The pre-implantation stage of cells will differentiate into one type of cell, while post-implantation stage of cells will turn into other types of cells. Their propensity toward specific cell types and growth properties are also different. The novel human pluripotent cells created by the scientists appear to represent the early stage of pluripotent cells — closer to well researched conventional mouse embryonic stem cells — and grow with better properties.

"The different behaviours of the pre- and post-implantation pluripotent stem cells means that findings from research done on mouse embryonic stem cells are often not translatable to work done on human embryonic stem cells," Ding says.

"With our new human pluripotent stem cells, we again have proof of principle that human stem cells can be created that are similar to mouse embryonic stem cells. The knowledge gained from mouse studies, therefore, will be more directly translatable to human cells, offering an advantage in biomedical research."
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ZenMaster

For more on stem cells and cloning, go to CellNEWS at
http://cellnews-blog.blogspot.com/ and
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Stem Cells Drug Testing Predicted to Boom under Obama

Stem Cells Drug Testing Predicted to Boom under Obama
Thursday, 18 December 2008

Embryonic stem cells could provide a new way of testing drugs for dangerous side effects, according to a leading British researcher.

Speaking at the British Pharmacological Society's Winter Meeting in Brighton today (Thursday, 18 December), Christine Mummery, Professor of Developmental Biology at Leiden University Medical Centre in The Netherlands, predicts that what is currently a small and sparsely funded research area will boom in coming years.

Her views have been buoyed by the victory of US President-elect Barack Obama, who is an ardent supporter of stem cell research. The researcher also believes the UK and Europe is well placed to be at the forefront of this exciting new research area.

Professor Mummery says that it typically costs $1 billion and takes 10 years to get a new drug to market. Before any tests or trials take place on patients, millions of chemical compounds are tested on cells in the laboratory, in a bid to detect adverse effects.

For potential drugs to treat heart disease, various cell types are used for the preliminary screening - but in the second round of testing, heart cells are necessary. At the moment the only way to do this is using heart cells from animals.

But Prof Mummery believes that since researchers are able to make unlimited human heart cells from embryonic stem cells, they offer a viable and scientifically exciting alternative.

"Many drugs meant to treat other complaints also have side effects on the heart, sometimes with fatal consequences. There are recent examples of drugs being withdrawn from the market because they caused sudden cardiac death in some patients,” she said.

"Regulators now require that drugs be tested for potential effects on the heart before going to market. At present the pharmaceutical industry has no alternative but to do this using heart cells from animals.”

"With the research that is now on-going in several parts of the world, including the UK, we believe using human heart cells from human embryonic stem cells can become a good and viable alternative. From a scientific point of view, it makes much more sense to use human stem cells to model human hearts."

Prof Mummery says the UK has already recognised the potential for stem-cell based drug testing by established a special public-private research programme called 'Stem Cells for Safer Medicine' or SC4SM.

"It is only a relatively small amount of money at present but it is a start. This is clearly an emerging field that will be of importance to the pharmaceutical industry, which has been reserved in embracing human embryonic stem cell technology until now because of the ethical objections from the US, where many of them have their main base,” she adds.

This is something that is expected to change very rapidly in the coming months following the election of Barack Obama.

"The UK has a head start in terms of being able to provide the technology. Working with partners across Europe, we think we can make a significant impact in terms of providing good assessment systems comparable with existing methods for predicting drug risk to the heart and discovering whether there are beneficial effects."

The potential for stem cell technology to be used in testing new drugs will be explored by both Prof Mummery and Dr Chris Denning, from the University of Nottingham, during a special symposium entitled, 'Mending a broken heart: advances and challenges of stem cell therapy,' at the British Pharmacological Society (BPS) Winter Meeting.

The symposium will also explore and discuss the challenges that lie ahead for those seeking to develop safe stem cell-based human therapies.

About the BPS
The British Pharmacological Society, including its Clinical Pharmacology Section, is the professional association for pharmacologists in the UK and is one of the leading pharmacological societies in the world.

The history of the Society dates back to 1931 when a group of pharmacologists met in Oxford and decided to form a learned society. Since those small beginnings the Society has grown to about 2,500 members, who work in academia, industry and the health services, and many are medically qualified. The Society covers the whole spectrum of pharmacology, including the laboratory, clinical and toxicological aspects.

The aims of the Society are to promote and advance pharmacology, including clinical pharmacology, by: assisting, promoting and encouraging research and providing a forum for the presentation of pharmacology; publishing the results of research; promoting and encouraging the education and training of pharmacologists; publishing material in various forms, and promoting and arranging conferences and meetings.
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ZenMaster

For more on stem cells and cloning, go to CellNEWS at
http://cellnews-blog.blogspot.com/ and
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Wednesday, 17 December 2008

'Hobbit' Fossil, Homo floresiensis, Represent a New Species

Researchers compare cranial features using 3-D modelling
Wednesday, 17 December 2008

University of Minnesota anthropology professor Kieran McNulty (along with colleague Karen Baab of Stony Brook University in New York) has made an important contribution toward solving one of the greatest paleoanthropological mysteries in recent history – that fossilized skeletons resembling a mythical "hobbit" creature represent an entirely new species in humanity's evolutionary chain.

Discovered on the Indonesian island of Flores in 2003, controversy has surrounded the fossilized hominid skeletons of the so-called "hobbit people," or Homo floresiensis ever since. Experts are still debating whether the 18,000-year-old remains merely belong to a diminutive population of modern-day humans (with one individual exhibiting "microcephaly," an abnormally small head) or represent a previously unrecognized branch in humanity's family tree.

Using 3D modelling methods, McNulty and his fellow researchers compared the cranial features of this real-life "hobbit" to those of a simulated fossil human (of similar stature) to determine whether or not such a species was distinct from modern humans.

"[Homo floresiensis] is the most exciting discovery in probably the last 50 years," said McNulty.

"The specimens have skulls that resemble something that died a million years earlier, and other body parts reminiscent of our three-million-year-old human ancestors, yet they lived until very recently – contemporaries with modern humans."

Comparing the simulation to the original Flores skull discovered in 2003, McNulty and Baab were able to demonstrate conclusively that the original "hobbit" skull fits the expectations for a small fossil hominid species and not a modern human. Their study was published online this month in the Journal of Human Evolution.

The cranial structure of the fossilized skull, says the study, clearly places it in humanity's genus Homo, even though it would be smaller in both body and brain size than any other member. The results of the study suggest that the theorized "hobbit" species may have undergone a process of size reduction after branching off from Homo erectus (one of modern day humanity's distant ancestors) or even something more primitive.

"We have shown with this study that the process of size reduction applied to fossil hominids accounts for many features seen in the fossil skull from Flores," McNulty said.

"It becomes much more difficult, therefore, to defend the hypothesis that the preserved skull is a modern human who simply suffered from an extremely rare disorder.”

Public interest in the discovery, analysis and implications of Flores "hobbits" has been high ever since 2003, inspiring several television specials (including a recent episode of "NOVA" entitled "Alien From Earth") and other media attention.

While the debate over Homo floresiensis will continue, McNulty believes this comprehensive analysis of the relationship between size and shape in human evolution is a critical step toward eventually understanding the place of the Flores "hobbits" in human evolutionary history.

"I think the majority of researchers favour recognizing this as a new species," McNulty said about the categorization of Homo floresiensis.

"The evidence is becoming overwhelming, and this study helps confirm that view."
.........

ZenMaster

For more on stem cells and cloning, go to CellNEWS at
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Most Women Report Satisfaction with Egg Donation

Some claim problems
Wednesday, 17 December 2008

Two-thirds of women who donated eggs to fertility clinics reported satisfaction with the process, but 16 percent complained of subsequent physical symptoms and 20 percent reported lasting psychological effects, according to the first study to examine the long-term effects of donation.

The research by scientists at the University of Washington included women who donated eggs at clinics in 20 states and is the largest study to explore the effects of donation in the United States, where the practice is not regulated.

"We don't know how many egg donors there are because no official records are kept and reporting is on a voluntary basis to the Centers for Disease Control and Prevention," said Nancy Kenney, UW associate professor of psychology and women studies and lead author of the study.

The researchers were surprised at the low number of women who reported an awareness of possible physical risk prior to donation. Nearly 63 percent viewed the potential physical risk as minor and 20 percent did not recall being made aware of physical risks at the time of their first donation.

"Many of these women may be forgetting that they were warned of the lesser risks, such as bloating and the discomfort from hormone injections," said Kenney.

"It has been quite a while since they read the material handed out by clinics or heard the risk lecture and it could be that they simple forgot. The age of the women also could be a factor. Risks don't mean much to young women. They may be discounting the risk. If you are 25 and are told that something may cause cancer when you are 45 that may seem to be forever."

Of those women who reported physical problems in the donation process, bloating, pain and cramping, ovarian hyper-stimulation, mood changes and irritability, and weight gain or loss were the most common complaints. Several women claimed infertility or decreased fertility or damage to their ovaries.

However, most of the women – 73 percent – reported being aware of some of psychological risks associated with egg donation prior to donating. These included the chance they might develop concern for or attachment to their eggs or to a potential or resulting offspring, concern that the donor or resulting child might want a future relationship with them, the possibility of having a genetic child in the world or the stress resulting from the donation process.

The women were split in their reasons for donating eggs. Nearly one-third (32 percent) said their motivations were completely based on helping others while almost 19 percent said financial concerns were their sole reason. The remainder cited a combination of altruistic and monetary factors for donation.

The research drew on the experiences of 80 women who donated eggs for the first time at least two years before filling out an 84-item questionnaire. Respondents donated eggs for the first time two to 15 years before completing the questionnaire and were an average of 30.6 years old when surveyed.

The study also found that:

The average payment was $3,965, with fees ranging from $1,104 to $7,313. (The most recent first donation year was 2002 and payments were converted to 2002 dollars).
Donors who said money was a very significant factor in donation received higher payments on average ($4,453) compared to those who said money was not important ($3,413).
Seventy percent of the women donated eggs more than once. Most repeat donors underwent the procedure two or three times. One woman donated eggs on nine occasions.
Forty-five percent of the women were students when they first donated.
Ninety-four percent of the students said financial compensation was a significant factor in deciding to donate compared to 57 percent of the women who were not students.
Most of the donations took place in California (23 percent), Massachusetts (7 percent), New York (7 percent), Washington (7 percent) and New Jersey (7 percent).

Kenney said a higher percentage of women who cited altruistic reasons as their primary motivation (84 percent) reported feeling happy about their donation experiences than did the women whose decisions were mainly financial (61 percent).

"We were asking these women years later and a feeling of helping may last longer than money," she said.

"We know if clinics don't offer money most women won't donate. Great Britain, where there is no paid egg donation program, for example, has a tremendous shortage of donors. But, as one of our donors said, 'if you do this just for money, you'll be sorry.'"

Kenney noted that a number of women offered suggestions to improve the donation process and complained about unequal treatment from clinics.

"Some women talked about how they were treated like delivery suppliers. Some clinics had separate entrances at the rear for donors and poorer waiting room facilities than for egg recipients. Some said they were handed a check at the end of he procedure and told 'see you around.' Others complained that they were offered limited extra health insurance for only a very limited time after a serious procedure," she said.

See also:
Human Ovulation Caught on Camera
CellNEWS - Wednesday, 18 June 2008

What is a human egg worth - £15 or US$10,000?
Monday, 25 November 2002

How much is a human egg worth?
CellNEWS - Wednesday, 21 February 2007

Back to the question: How much is a human egg worth?
CellNEWS - Tuesday, 09 October 2007

Most egg cells in a female body die naturally
CellNEWS - Tuesday, 24 July 2007

Newcastle First to Pay for Human Eggs
CellNEWS - Wednesday, 09 January 2008

.........

ZenMaster

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Monday, 15 December 2008

Single Adult Muscle Stem Cell Can Self Renew

Single Adult Muscle Stem Cell Can Self Renew
Monday, 15 December 2008

The first demonstration that a single adult stem cell can self-renew in a mammal was reported at the American Society for Cell Biology (ASCB) 48th Annual Meeting, Dec. 13-17, 2008 in San Francisco.

The transplanted adult stem cell and its differentiated descendants restored lost function to mice with hind limb muscle tissue damage.

The adult stem cells used in the study, conducted at Stanford University, were isolated from a mixed population of satellite cells in the skeletal muscle of mice.

The skeletal adult muscle stem cells (MusSC), which live just under the membrane that surrounds muscle fibres, normally respond to tissue damage by giving rise to progenitor cells that become myoblasts, fusing into myofibers to repair the tissue damage.

The scientists transplanted the MusSC into special immune-suppressed "nude" mice whose muscle satellite cells had been wiped out in a hind limb by irradiation.

The mice would only be able to repair injury if the transplanted MuSC "took." The scientists, Alessandra Sacco and Helen Blau, had genetically engineered the transplanted MusSC to express Pax7 and luciferase proteins. As a result, every transplanted cell glowed under ultraviolet light and was easy to trace.

"To be able to detect the presence of the cells by bioluminescence was really a breakthrough," says Blau.

"It taught us so much more. We could see how the cells were responding, and really monitor their dynamics."

Through luminescent imaging as well as quantitative and kinetic analyses, Sacco and Blau tracked each transplanted stem cell as it rapidly proliferated and engrafted its progeny into the irradiated muscle tissue.

The scientists then injured the regenerated tissue, setting off massive waves of muscle cell growth and repair, and subsequently showed that the MuSC and descendents rescued the second animal's lost muscle healing function.

After isolating the luciferase-glowing muscle stem cells from the transplanted animal, the scientists duplicated, or cloned, the cells in the lab. Like the original MuSC, the cloned copies were intact and capable of self-renewal.

"We are thrilled with the results," says Sacco.

"It's been known that these satellite cells are crucial for the regeneration of muscle tissue, but this is the first demonstration of self-renewal of a single cell."

The ability to isolate and then transplant skeletal adult muscle stems cells could have a wide impact in treating not only a variety of muscle wasting diseases such as muscular dystrophy but also severe muscle injuries or loss of function from aging and disuse.

In other experiments, the researchers transplanted between 10 and 500 luciferase-tagged MuSC into the leg muscles of mice.

These cells also proliferated and engrafted, forming new myofibers and fusing with injured fibres.

Unlike tumour cells, the transplanted stem cells achieved homeostasis, growing to a stable, constant level and ceasing replication.

After demonstrating that the transplanted stem cells proliferated and fully restored the animal's lost function, Sacco and Blau recovered new stem cells from the transplant with full stem cell potency, meeting the final "gold standard" test for adult multipotent stem cells.
.........

ZenMaster

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Heart Regenerates after Infarction

First trials with mice
Monday, 15 December 2008

Up until today scientists assumed that the adult heart is unable to regenerate. Now, researchers and cardiologists from the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch and the Charité – Universitätsmedizin Berlin (Germany) have been able to show that this dogma no longer holds true. Dr. Laura Zelarayán and Assistant Professor Dr. Martin W. Bergmann were able to show that the body’s own heart muscle stem cells do generate new tissue and improve the pumping function of the heart considerably in an adult organism, when they suppress the activity of a gene regulator known as beta-catenin in the nucleus of the heart cells.

The gene regulator beta-catenin plays an important role in the development of the heart in embryos. Dr. Zelarayán and Dr. Bergmann could now show that beta-catenin is also important for the regeneration of the adult heart. They suppressed this factor in the nucleus of the heart cells in mice.

This way they activated heart precursor cells (stem cells) to turn on the regeneration of heart in adult mice. Four weeks after blocking beta-catenin, the pumping function of the heart of the animals had improved and the mice survived an infarction much better than those animals with a functioning beta-catenin gene. An important contribution to this project has been a transgenic mouse line generated by Professor Walter Birchmeier`s (MDC) laboratory.

Markers identified for Heart Muscle Stem Cells
In addition, the researchers have proven that heart muscle stem cells exist. So far, these cells had not been characterized clearly. They could demonstrate that two markers for heart cells – the structural protein alpha myosin heavy chain and the transcription factor Tbx5 - are also expressed on heart precursor cells.

"The evidence of cells with these markers in the adult heart demonstrates that stem cells dating back from heart development survive in niches in the adult heart", Dr. Bergmann explains.

The researchers in Germany collaborated with scientists in the Netherlands and Belgium. For this research, Dr. Bergmann was awarded the Wilhelm P. Wintersteinpreis this summer. The research group of Dr. Bergmann, a guest researcher at the MDC who recently became Deputy of the Department of Cardiology at the Asklepios Clinic St. Georg in Hamburg, belongs to the research group of Professor Rainer Dietz (MDC and Charité).

Reference:
Beta-catenin downregulation attenuates ischemic cardiac remodeling through enhanced resident precursor cell differentiation
Laura Zelarayán, Claudia Noack, Belaid Sekkali, Jana Kmecova, Christina Gehrke, Anke Renger, Maria-Patapia Zafiriou, Roel van der Nagel, Rainer Dietz, Leon J. de Windt, Jean-Luc Balligand and Martin W. Bergmann
PNAS, online December 10, 2008, doi: 10.1073/pnas.0808393105
.........

ZenMaster

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Functional Stem-cell Niche Model Created

Functional Stem-cell Niche Model Created
Monday, 15 December 2008

Like it or not, your living room probably says a lot about you. Given a few uninterrupted moments to poke around, a stranger could probably get a pretty good idea of your likes and dislikes, and maybe even your future plans. Scientists at the Stanford University School of Medicine employing a similar "peeping Tom" tactic to learn more about how stem cells develop have taken a significant step forward by devising a way to recreate the cells' lair — a microenvironment called a niche — in an adult animal.

"We have isolated the cells in mouse bone that make bone and cartilage from scratch and attract wandering blood stem cells," said Irving Weissman, MD, the Virginia & D.K. Ludwig Professor for Clinical Investigation in Cancer Research and the director of Stanford's Institute for Stem Cell Biology and Regenerative Medicine.

"The stem cells can and do settle in these 'niches' and make blood that is exported to the body."

The research marks the first time that scientists have successfully recreated a functional stem-cell niche for further study. Weissman and his colleagues plan to use the model system to determine how the niche environment interacts with the blood stem cells to affect their development and fate, and how leukaemia’s respond to these niches. They will also investigate the bone and cartilage healing capacity of these cells.

Weissman is the senior author of the study, which will be published Dec.10 in the advance online issue of Nature. Graduate student Charles Chan shares first authorship with postdoctoral scholars Ching-Cheng Chen, PhD, and Cynthia Luppen, PhD.

Blood-forming stem cells typically reside in the bone marrow. The researchers found that a specific subset of foetal mouse bone cells could not only take up residence and produce bone when injected near the kidney of an adult animal, but they also generated a bone marrow cavity that sheltered host-derived blood stem cells. In contrast, other subsets of foetal bone cells generated only bone.

"An amazing part of this study was the formation of organized bone, cartilage and blood stem cell niches from an initially dispersed set of cells," said Weissman, who is also a member of the Stanford Cancer Center.

"If we can find the daughter cell in this population that is responsible for niche formation, we may learn enough to eventually be able to expand blood stem cell numbers so that a small number, say from umbilical cord blood, can be made into enough to treat several patients with failure of blood formation."

Suppressing the expression of factors involved in a specialized bone-building process called endochondrial ossification in the host mouse stopped the formation of the marrow cavity and the recruitment of host stem cells. Using similar foetal bone cells from parts of the skeleton that do not undergo the process — such as the skull and the jaw — also blocks cavity formation. The findings suggest that endochondrial ossification is a necessary step in setting up house for stem cells.
.........

ZenMaster

For more on stem cells and cloning, go to CellNEWS at
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Fat Cells Restore Function after Spinal Cord Injury

Fat cells treat spinal cord injury
Monday, 15 December 2008

A study published in the current issue of Cell Transplantation (Vol.17, No. 8) suggests that mature adipocytes - fat cells - could become a source for cell replacement therapy to treat central nervous system disorders.

According to the study's lead researcher, Dr. Yuki Ohta of the Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Japan, adipose-derived stem/stromal cells have in the past been shown to differentiate into neuronal cells in an in vitro setting. In their study, for the first time fat cells have been shown to successfully differentiate into neuronal cells in in vivo tests. The fat cells are grown under culture conditions that result in them becoming de-differentiated fat (DFAT) cells.

"These cells, called DFAT cells, are plentiful and can be easily obtained from adipose tissue without discomfort and represent autologous (same patient) tissue," said Ohta.

"DFAT cells, with none of the features of adipocytes, do have the potential to differentiate into endothelial, neuronal or glial lineages."

The research team reported that DFAT cells expressed neurotrophic factors, such as BDNF and GDNF, prior to and after transplantation and which likely contributed to the promotion of functional recovery.

According to Ohta and colleagues, tests in animal models confirmed that the injected cells survived without the aid of immunosuppression drugs and that the DFAT-grafted animals showed significantly better motor function than controls.

"We concluded that DFAT-derived neurotrophic factors contributed to promotion of functional recovery after spinal cord injury (SCI)," said Ohta.

"Transplanting DFAT cells into SCI rats significantly promoted the recovery of their hind limb function."

"These studies demonstrate the ability to obtain stem cells from a patient's own fat that can help repair injury to the spinal cord," said Paul R. Sanberg, PhD, DSc, at the University of South Florida Health, and Coeditor-in-chief of Cell Transplantation.
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ZenMaster

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Sunday, 7 December 2008

The Beauty of Cell Division

The Beauty of Cell Division
Sunday, 07 December 2008

Cell division is one of the most fundamental processes of life. It explains how one cell can give rise to an organism of several million cells, it determines the shape of different life forms and it underpins our body's capacity to heal when injured. Often we only notice how important cell division really is when it goes wrong and results in cancer or other diseases. But apart from being crucial for biology, cell division is also a very beautiful process as these images taken by Joël Beadouin in the group of Jan Ellenberg at the European Molecular Biology Laboratory show.

The pictures were taken through a confocal microscope and show the different steps of cell division in a human cell magnified approximately 650 times.

Credit: Joël Beadouin, EMBL

From left to right: When not dividing, the genetic material of a cell (DNA in blue) is found loosely in the nucleus, where a second copy of it is made in preparation for division. At the onset of division, the DNA condenses into distinct chromosomes, the nucleus breaks down and protein filaments called microtubules (green) form a spindle apparatus. The spindle aligns the chromosomes in the middle of the cell and in the next step pulls a copy of each chromosome towards the opposite poles of the cell. After this division of the genetic material, or mitosis, is completed, the rest of the cell divides. A band formed by another type of protein filaments, called actin (red), squeezes the mother cell in half to create two identical daughters. The whole process takes approximately 90 minutes.

The images were taken as part of Mitocheck, an international research project funded by the European Commission that tries to identify and characterize all the genes necessary for cell division in human cells.
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ZenMaster

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Friday, 5 December 2008

A Little Wine Boosts Omega-3 in the Body

Researchers find a novel mechanism for a healthier heart
Friday, 05 December 2008

Results from the European study IMMIDIET show that moderate wine intake is associated with higher levels of omega-3 fatty acids considered as protective against coronary heart disease

Moderate alcohol intake is associated with higher levels of omega-3 fatty acids in plasma and red blood cells. This is the major finding of the European study IMMIDIET that will be published in the January issue of the American Journal of Clinical Nutrition, an official publication of the American Society for Nutrition. The study suggests that wine does better than other alcoholic drinks. This effect could be ascribed to compounds other than alcohol itself, representing a key to understand the mechanism lying behind the heart protection observed in moderate wine drinkers.

The IMMIDIET study examined 1,604 citizens from three geographical areas: south-west London in England, Limburg in Belgium and Abruzzo in Italy. Thanks to a close cooperation with General Practitioners of these areas, all participants underwent a comprehensive medical examination, including a one year recall food frequency questionnaire to assess their dietary intake, alcohol consumption included.

Omega-3 fatty acids, mainly derived from fish, are considered as protective against coronary heart disease and sudden cardiac death, thus their high blood concentration is definitely good for our health.

Now European researchers found that moderate alcohol drinking acts like a 'trigger', boosting the amount of omega-3 fatty acids in our body.

"Several studies have shown that moderate alcohol consumption, including wine, is associated with protection against coronary heart disease and ischemic stroke,” says Romina di Giuseppe, lead author of the study, from the Research Laboratories at Catholic University of Campobasso.

“Although the mechanisms are not completely defined, there was some evidence that alcohol intake might influence the metabolism of essential polyunsaturated fatty acids, as omega-3. That is exactly what we found in our population study. People drinking moderate amounts of alcohol, one drink a day for women and two for men, had higher concentration of omega-3 fatty acids in plasma and red blood cells independently of their fish intake".

However important these results appear to be, the best is yet to come. Researchers from Catholic University of Campobasso, in Italy, and from University of Grenoble, in France, turned their attention on the variety of alcoholic beverages consumed in order to see whether the high levels of omega-3 fatty acids detected might be ascribed to alcohol itself or to other substances.

"From our previous studies we know that association between wine drinking and increased concentration of omega-3 fatty acids have been observed,” says Michel de Lorgeril, from the University of Grenoble, partner of the IMMIDIET project and co-leader of the study.

“Nevertheless, it was not possible to separate the effects of wine from those of beer or spirits. Our study of 3 populations with different dietary habits and different consumption of alcoholic beverages types allowed us to explore this aspect."

"Analysis carried out on different alcoholic beverages,” argues Licia Iacoviello coordinator of the IMMIDIET study at Catholic University of Campobasso, “showed that the association between alcohol and omega-3 fatty acids was present in both wine drinkers and beer or spirits drinkers. However, the association was stronger between wine drinking and omega-3 fatty acids levels. This suggests that components of wine other than alcohol is associated with omega-3 fatty acids concentration. We may guess this effect can be ascribed to polyphenols".

Polyphenols are naturally occurring compounds contained in a different variety of food and beverages, such as wine. Due to their strong antioxidant activity, they are able to reduce oxidation processes caused by free radicals.

"We consider these data to be a major finding," de Lorgeril concludes, "opening a new window in the field of cardiovascular prevention. Beyond the alcohol issue, our results raise crucial questions regarding the effects of polyphenols on lipids (both in blood and cell membranes) and possibly of lipids on polyphenols".

About The IMMIDIET study:
Funded by the European Union under Key Action 1: Food, Nutrition and Health QLK1-CT-2000-00100, IMMIDIET aims to acquire fundamental knowledge in the field of cardiovascular disease, especially regarding the interaction between genetics and lifestyle.

At the core of the study, there is an important episode of Italian migration: Belgium, a country that became the new home for thousands of Italians, mostly from the Abruzzo region, who came to work in the mines. Many of those emigrants did not come back to Italy but remained in their new country. Some of them married a Belgian partner. Their genes remained the same, of course, but how much "Italy" is still there in their diet? And how much did they transmit it to their spouses? Moreover, how many Italian emigrants assimilate dietary habits of the country in which they were guests? In this framework, the role of genetic factors and lifestyle can be assessed to explore new ways in prevention of cardiovascular diseases.

To carry on the research, married couples have been recruited in three European areas: South-East London in England, Limburg in Belgium and Abruzzo in Italy. In the first phase of the study the couples involved were formed by people from the same area, Italians married with Italians (in the Abruzzo region), Belgians married with Belgians (in the Limburg area) and English married with English (in the South-East part of London)".

The second phase of IMMIDIET recruited mixed Italian–Belgian couples to understand if, acquiring dietary habits from Abruzzo, the Belgian partner changed his own risk regarding heart diseases.
.........

ZenMaster

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Dormant Stem Cells for Emergencies

Dormant Stem Cells for Emergencies
Friday, 05 December 2008

Many specialized cells, such as in the skin, intestinal mucosa or blood, have a lifespan of only a few days. For these tissues to function, a steady replenishment of specialized cells is indispensable. This is the task of so-called "adult" stem cells also known as tissue stem cells.

Stem cells have two main characteristics: First, they are able to differentiate into all the different cell types that make up their respective tissue – a property called pluripotency. Second, they need to renew themselves in order to be able to supply new specialized tissue cells throughout life. These processes have best been studied in mouse bone marrow.

Up to now, scientists have assumed that adult stem cells have a low division rate. According to theory, they thus protect their DNA from mutations, which happen particularly during cell division and can lead to transformation into tumour stem cells. However, the actual number of divisions of a blood stem cell throughout an organism's lifespan has remained unknown.

Professor Dr. Andreas Trumpp and Dr. Anne Wilson have now discovered a group of stem cells in mouse bone marrow that remain in a kind of dormancy almost throughout life. Trumpp, who has been head of the Cell Biology Division at DKFZ since summer 2008, had carried out these studies at the Ecole Polytechnique Fédérale in Lausanne, Switzerland, jointly with colleagues at the Ludwig Institute for Cancer Research located in the same city.

The scientists labelled the genetic material of all mouse blood cells and subsequently investigated how long this label is retained. With each division, the genetic material is apportioned to the daughter cells and, thus, the labelling dilutes. During these studies, the investigators discovered the dormant stem cells which divide only about five times throughout the life of a mouse. Translated to humans, this would correspond to only one cell division in 18 years. Most of the time, these cells, which constitute no more than about 15 percent of the whole stem cell population, remain in a kind of dormancy with very low metabolism. In contrast, stem cells of the larger group, the "active" stem cells, divide continuously about once a month.

However, in an emergency such as an injury of the bone marrow or if the messenger substance G-CSF is released, the dormant cell population awakes. Once awakened, it shows the highest potential for self-renewal ever to be observed in stem cells. If transplanted into irradiated mice, these cells replace the destroyed bone marrow and restore the whole hematopoietic system. It is possible to isolate new dormant stem cells from the transplanted animals and these cells are able to replace bone marrow again – this can be done several times in a row. The situation is different with "active" stem cells, where bone marrow replacement can successfully be carried out only once.

"We believe that the sleeping stem cells play almost no role in a healthy organism," Trumpp explains.

"The body keeps its most potent stem cells as a secret reserve for emergencies and hides them in caves in the bone marrow, also called niches. If the bone marrow is damaged, they immediately start dividing daily, because new blood cells are needed quickly."

Once the original cell count is restored and the bone marrow is repaired, these stem cells go back to deep sleep. The larger population of "active" stem cells, however, keeps up the physiological balance of blood cells in the normal healthy state.

Andreas Trumpp expects that these results may give valuable impetus to our understanding of cancer stem cells.

"Cancer stem cells, too, probably remain in a dormant state most of the time – we think that this is one of the reasons why they are resistant to many kinds of chemotherapy that target rapidly growing cells. If we were able to wake up these sleepers before a patient receives treatment, it might be possible to also eliminate cancer stem cells for the first time and, thus, to treat the disease much more effectively by destroying the supply basis."

In a second article, Dr. Elisa Laurenti from Trumpp's team shows that the two cancer genes c-Myc and N-Myc play a vital role in the functioning of stem cells. The two genes provide the blueprints for what are called transcription factors, which in turn regulate the activity of other genes and are overactive particularly in cancer cells. If both c-Myc and N-Myc are switched off at the same time in mice, the animals quickly start suffering from a general lack of blood cells and quickly die.

The two genes are not only responsible for survival of nearly all blood cells, but they also jointly control the two prime characteristics of stem cells – the capability of self-renewal and the potential to produce differentiated blood cells. This result is not only relevant for our understanding of stem cells, but it also explains the damage that can be caused by overactive Myc genes.

"In tumours, too, c-Myc and N-Myc are presumably responsible for the self-renewal of cancer stem cells and, thus, for uncontrolled growth," Trumpp explains.

References:
Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair.
Anne Wilson; Gabriela Oser; Richard van der Wath; William Blanco; Elisa Laurenti; Maike Jaworski; Cyrille Durant; Leonid Eshkind; Ernesto Bockamp; Pietro Lio; Robson MacDonald, and Andreas Trumpp
Cell 2008, DOI 10.1016/j.cell.2008.10.048

Hematopoietic Stem Cell Function and Survival Depend on c-Myc and N-Myc Activity.
Elisa Laurenti, Barbara Varnum-Finney, Anne Wilson, Isabel Ferrero, William E. Blanco-Bose, Armin Ehninger, Paul S. Knoepfler, Pei-Feng Cheng, H. Robson MacDonald, Robert N. Eisenman, Irwin D. Bernstein, and Andreas Trumpp
CellL Stem Cell 2008, DOI 10.1016/j.stem.2008.09.005
.........

ZenMaster

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What to Do With Leftover Embryos?

Largest study of fertility patients shows concerns about embryo disposition
Friday, 05 December 2008

Fertility patients who are done having children feel responsible for the stored, frozen embryos left over from their treatment, yet more than half are against implanting the embryos in anyone else, according to a new study by researchers at Duke University Medical Center.

"This really turns our moral presumptions on their heads," says Anne Drapkin Lyerly, MD, an obstetrician/gynaecologist and bioethicist at Duke, and lead investigator of the findings that appear online in Fertility & Sterility.

"Parents care very much about what happens to their embryos, but that doesn't mean they want them to become children. Our study shows that many feel they have to do what they can to prevent their embryo from becoming a child."

The survey of more than 1,000 fertility patients is the largest and only multi-site study to shed important light on the state of the nation's 500,000 frozen embryos currently in storage. It reveals previously unexplored concerns that patients have about their embryos, and it comes at a time when several states and even the federal government are attempting to enact legislation that would either assert an embryo is a person, allow abandoned embryos to be adopted by another couple, or allow unused embryos to become "wards of the state."

What to do with those unused embryos has also become a sticking point for providers, since they are held responsible for safe storage or disposition of apparently abandoned embryos.

Fresh embryos are used in more than 80% of fertility treatment cycles, but most patients also choose to freeze some embryos that were created but not implanted, to use as a possible backup. This means that extra embryos often remain after treatment is completed. Previous studies have found that when childbearing is complete, as many as 70 percent of patients put off for five years — or more — the decision of what to do with those frozen embryos, even while they continue to pay annual storage fees. In Lyerly's study, 20 percent of the patients who had completed childbearing indicated they were likely to freeze their embryos "forever."

The lack of acceptable options fuels patients' reluctance to make a decision.

"Either the options they prefer aren't available or they are unacceptable," explains Lyerly.

In the survey, the researchers presented four embryo disposition options: thawing and discarding; reproductive donation; indefinite freezing; and donation for research. The majority were unlikely to choose any of these options except for one: research donation.

In a previous paper published in Science, Lyerly reported that 60 percent would be likely to donate unused embryos for stem cell research, an option not readily available. But even if federal policies on funding stem cell research change, Lyerly says that doesn't solve patients' conundrum.

"For many of these patients, the need to make a decision about disposing these embryos is not discussed up front. Understandably, fertility patients have hard times thinking about destroying their embryos when they are emotionally and financially invested in trying to make a baby," she says.

The conundrum arises when reproductive goals change without a renewed discussion about what to do with the embryos that have been stored.

"Many centres don't make available all the options for disposition," Lyerly says.

"Even in places where embryo research is not conducted, it's possible that embryos can be transferred to another centre, yet this might not be discussed."

Two methods that were considered somewhat acceptable by about 20 percent of the fertility patients were placement of embryos in a woman's body at an infertile time, and the idea of a ritual disposal ceremony. Yet, Lyerly says these alternatives are rarely offered to patients even though "these may be the answers to many patients' desires as they allow the embryos to pass in a way that seems most respectful to them."

By bringing fertility patients' concerns to the forefront, Lyerly hopes the next step will be the development of clinical guidelines and ongoing informed consent processes for patients at various stages of fertility treatment. She also hopes it will encourage more detailed disclosure about the available disposition options and facilitate broad availability of disposition decisions that are morally acceptable to the majority of fertility patients.
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Endothelial Cells Give Rise to Blood Stem Cells

UCLA discovery could lead to new treatments for blood disorders, cancers
Friday, 05 December 2008

Stem cell researchers at UCLA have proven definitively that blood stem cells are made during mid-gestational embryonic development by endothelial cells, the cells that line the inside of blood vessels.

While the anatomic location in the embryo where blood stem cells originate has been well documented, the cell type from which they spring was less understood. The UCLA finding, published in the Dec. 4, 2008 issue of the journal Cell Stem Cell, puts to rest a long-standing controversy over whether blood stem cells were created, or born, in the endothelium or originated from another cell type in a nearby location.

Researchers from the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA used a cell fate tracing technique to identify the source of blood stem cells. They genetically marked endothelial cells to discover what other cells they gave rise to and where those cells migrated to in the body.

"We genetically traced the endothelial cells to find out what they became over time," said Luisa Iruela-Arispe, senior author of the paper, a professor of molecular, cell and developmental biology and director of the Cancer Cell Biology Program Area at UCLA's Jonsson Comprehensive Cancer Center.

"In that way, we were able to understand that, within the embryo, endothelial cells were responsible for the generation of blood stem cells. They make blood, they aren't just the pipes that carry it."

The finding ultimately could lead to new therapies for certain blood disorders and cancers, said Ann Zovein, the first author of the study and a California Institute for Regenerative Medicine-Broad Stem Cell Research Center Training Grant postdoctoral fellow in Iruela-Arispe's lab.

Blood stem cells currently cannot be grown outside of the body without losing their "stemness," meaning they then differentiate into the different cells that make up blood, including red blood cells, white blood cells and platelets. If blood stem cells can be gown outside the body from endothelial cells and only self-renew, or make more of their own kind, researchers may one day be able to reprogram blood vessel cells to produce blood stem cells to replace the bone marrow in transplants or the mutated blood cells that result in diseases like leukaemia.

"We found that endothelial cells are capable of making blood stem cells within embryonic areas that prevent differentiation into other lineages," Zovein said.

"In trying to understand how blood stem cells arise from the endothelium, we may learn enough to be able to grow pure, designer blood stem cells outside the human body."

For example, researchers may some day be able to take a blood vessel from a patient and grow blood stem cells specific to that patient, which could be used for bone marrow transplantation. Since the blood stem cells originated from the patient, there would be no need to find a matching donor to provide the marrow. The cells also could be used to replace diseased cells that result in cancer, providing a new way to treat malignancies such as leukaemia.

The creation of blood stem cells by endothelial cells occurs at a specific time in embryonic development and researchers want to know what takes place biologically during that period, what specific cell signalling pathways are sending the messages to make blood stem cells. Iruela-Arispe and her team hope to mimic the embryonic environment in the lab to create blood cells that don't differentiate.

"Next we need to understand what signalling mechanisms are at work that allow endothelial cells to make blood stem cells," Iruela-Arispe said.

"We need to find out how we can program the endothelial cells to make blood stem cells, what's important in the embryonic blood vessel wall that allows for this phenomenon and whether we can reprogram adult blood vessels to do the same thing."

While this study was done in mouse models, Iruela-Arispe and her team will be working with human endothelial cells to confirm their work and further uncover the cell signalling mechanisms in play.

About Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA:
The stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the centre. With more than 150 members, the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research is committed to a multi-disciplinary, integrated collaboration of scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The institute supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed towards future clinical applications to treat disease. The centre is a collaboration of the David Geffen School of Medicine, UCLA's Jonsson Cancer Center, the Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science.

Reference:
Fate Tracing Reveals the Endothelial Origin of Hematopoietic Stem Cells
Ann C. Zovein, Jennifer J. Hofmann, Maureen Lynch, Wendy J. French, Kirsten A. Turlo, Yanan Yang, Michael S. Becker, Lucia Zanetta, Elisabetta Dejana, Judith C. Gasson, Michelle D. Tallquist, M. Luisa Iruela-Arispe
Cell Stem Cell, Volume 3, Issue 6, 625-636, 4 December 2008, doi:10.1016/j.stem.2008.09.018
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ZenMaster

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Monkey Skin Cells Reprogrammed into Stem Cells

What’s good for the mouse is good for the monkey
Friday, 05 December 2008

Scientists have successfully created the first induced pluripotent stem (iPS) cell lines from adult monkey skin cells. The research, published by Cell Press in the December issue of the journal Cell Stem Cell, demonstrates that the method of direct reprogramming is conserved among species and may be useful for creation of clinically valuable primate models for human diseases.

Although previous work has shown that induction of four key transcription factors can reprogram adult mouse and human skin cells into iPS cells, creation of iPS cells in other species has not been demonstrated.

"We sought to generate monkey iPS cells from skin cells isolated an adult male rhesus macaque using the predicted monkey transcription factors OCT4, SOX2, KLF4 and c-MYC," explains Dr. Hongkui Deng from the Key Laboratory of Cell Proliferation and Differentiation at Peking University in Beijing, China.

Dr. Deng and colleagues used retroviruses expressing these four factors to infect adult monkey skin cells. This technique led to creation of cells that displayed multiple hallmarks of embryonic stem (ES) cells. Specifically, the cells exhibited physical characteristics associated with ES cells, expressed genes appropriate for ES cells and possessed the ability to develop into multiple types of differentiated cells. These results reveal that monkey iPS cells can be generated using the same four transcription factors that have been used to successfully create mouse and human iPS cells.

The work has multiple exciting applications.

"As the rhesus macaque is the most relevant primate model for most human diseases, highly efficient generation of monkey iPS cells would allow investigation of the treatment of various diseases in this model," offers Dr. Deng.

"In addition, direct reprogramming with the four transcription factors could be a universal strategy for generating iPS cells in other species."

Reference:
Generation of Induced Pluripotent Stem Cells from Adult Rhesus Monkey Fibroblasts
Haisong Liu, Fangfang Zhu, Jun Yong, Pengbo Zhang, Pingping Hou, Honggang Li, Wei Jiang, Jun Cai, Meng Liu, Kai Cui, Xiuxia Qu, Tingting Xiang, Danyu Lu, Xiaochun Chi, Ge Gao, Weizhi Ji, Mingxiao Ding, Hongkui Deng
Cell Stem Cell, Volume 3, Issue 6, 587-590, 4 December 2008, doi:10.1016/j.stem.2008.10.014

See also:
Guidelines and Techniques for the Generation of Induced Pluripotent Stem Cells
Nimet Maherali and Konrad Hochedlinger
Cell Stem Cell, Volume 3, Issue 6, 595-605, 4 December 2008, doi:10.1016/j.stem.2008.11.008
.........

ZenMaster

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Gene Therapy Corrects Sickle Cell Disease in Laboratory

New St. Jude treatment alleviates long-term anaemia and organ damage in mice and paves the way for human applications
Friday, 05 December 2008

Using a harmless virus to insert a corrective gene into mouse blood cells, scientists St. Jude Children's Research Hospital have alleviated sickle cell disease pathology. In their studies, the researchers found that the treated mice showed essentially no difference from normal mice. Although the scientists caution that applying the gene therapy to humans presents significant technical obstacles, they believe that the new therapy will become an important treatment for the disease.

Sickle cell disease, which affects millions of people worldwide, arises because of a tiny genetic defect in the gene for beta-globin, a protein component of haemoglobin. This defect causes haemoglobin-containing red blood cells to tend to deform, clump and break apart. The resulting clogged blood vessels can lead to cognitive dysfunction by causing small strokes in the brain and cause damage to kidneys, liver, spleen and lungs. The only permanent cure for the disease is a bone marrow transplant to give recipients blood-forming cells that will form normal beta-globin. However, such transplants are rare because of the lack of compatible donors.

Researchers have long known that symptoms of the disease could be alleviated by persistence in the blood of an immature foetal form of haemoglobin in red blood cells. This immature haemoglobin, which usually disappears after birth, does not contain beta-globin, but another form called gamma-globin. St. Jude researchers had found that treating patients with the drug hydroxyurea encourages the formation of foetal haemoglobin and alleviates disease symptoms.

"While this is a very useful treatment for the disease, our studies indicated that it might be possible to cure the disorder if we could use gene transfer to permanently increase foetal haemoglobin levels," said Derek Persons, M.D., Ph.D., assistant member in the St. Jude Department of Hematology.

He and his colleagues developed a technique to insert the gene for gamma-globin into blood-forming cells using a harmless viral carrier. The researchers extracted the blood-forming cells, performed the viral gene insertion in a culture dish and then re-introduced the altered blood-forming cells into the body. The hope was that those cells would permanently generate red blood cells containing foetal haemoglobin, alleviating the disease.

In the experiments, reported in the advanced, online issue of the journal Molecular Therapy, the researchers used a strain of mouse with basically the same genetic defect and symptoms as humans with sickle cell disease. The scientists introduced the gene for gamma-globin into the mice's blood-forming cells and then introduced those altered cells into the mice.

The investigators found that months after they introduced the altered blood-forming cells, the mice continued to produce gamma-globin in their red blood cells.

"When we examined the treated mice, we could detect little, if any, disease using our methods," said Persons, the paper's senior author.

"The mice showed no anaemia, and their organ function was essentially normal."

The researchers also transplanted the altered blood-forming cells from the original treated mice into a second generation of sickle cell mice to show that the gamma-globin gene had incorporated itself permanently into the blood-forming cells. Five months after that transplantation, the second generation of mice also showed production of foetal haemoglobin and correction of their disease.

"We are very encouraged by our results," Persons said.

"They demonstrate for the first time that it is possible to correct sickle cell disease with genetic therapy to produce foetal haemoglobin. We think that increased foetal haemoglobin expression in patients will be well tolerated and the immune system would not reject the haemoglobin, in comparison to other approaches."

While Persons believes that the mouse experiments will lead to treatments in humans, he cautioned that technical barriers still need to be overcome.

"It is far easier to achieve high levels of gene insertion into mouse cells than into human cells," he said.

"In our mouse experiments, we routinely saw one or two copies of the gamma-globin gene inserted into each cell. However, in humans this insertion rate is at least a hundred-fold less."

Persons' laboratory is currently working with other animal and human cells to develop methods to achieve a high enough gene insertion rate to make the gene therapy clinically useful.

About St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization.
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ZenMaster

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http://cellnews-blog.blogspot.com/ and
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New 'Control Knobs' for Stem Cells Identified

Tufts study shows that changes in membrane voltage control timing of differentiation in adult stem cells
Friday, 05 December 2008

Natural changes in voltage that occur across the membrane of adult human stem cells are a powerful controlling factor in the process by which these stem cells differentiate, according to research published by Tufts University scientists.

Tufts doctoral student Sarah Sundelacruz, Professor of Biology Michael Levin, and Chair of Biomedical Engineering David L. Kaplan published their paper "Membrane Potential Controls Adipogenic and Osteogenic Differentiation of Mesenchymal Stem Cells" in the November 17, 2008, issue of PLoS ONE.

"We have found that voltage changes act as a signal to delay or accelerate the decision of a stem cell to drop out of a stem state and differentiate into a specific cell type. This discovery gives scientists in regenerative medicine a new set of control knobs to use in ongoing efforts to shape the behavior of adult stem cells," said Levin.

"In addition, by uncovering a new mechanism by which these cells are controlled in the human body, this research suggests potential future diagnostic applications."

Harnessing the potential of stem cells for applications such as wound healing and tissue regeneration is a tantalizing yet daunting task. Although many studies indicate that electrophysiology plays a crucial role in cell proliferation and differentiation, its functional role in stem cell biology is poorly understood.

The Tufts researchers studied the changes in membrane potential (voltage across the membrane) shown by human mesenchymal stem cells (hMSCs) obtained from donor bone marrow as the hMSCs were differentiating into fat and bone cells. They found that hyperpolarisation (increased difference between the voltage in the interior and exterior of a cell) was characteristic of differentiated cells compared with undifferentiated cells and that hMSCs show different membrane potential profiles during bone vs. fat differentiation.

To determine whether hyperpolarisation was functionally required for differentiation, the scientists depolarized the hMSCs by exposing them either to high levels of extracellular potassium ions or to ouabain, a compound that blocks the transfer of ions in and out of cells. Both treatments disrupted the normal increase in negative voltage that occurs during differentiation and suppressed fat and bone cell differentiation markers.

In contrast, treatment with hyperpolarizing reagents up-regulated bone cell markers – indicating that voltage changes are not merely permissive for differentiation but can act as an instructive signal to either induce or inhibit differentiation.

More study is needed to determine whether hyperpolarisation also determines which specific type of cell stem cells will differentiate into, according to the Tufts researchers.

About Tufts University:
Tufts University, located on three Massachusetts campuses in Boston, Medford/Somerville, and Grafton, and in Talloires, France, is recognized among the premier research universities in the United States. Tufts enjoys a global reputation for academic excellence and for the preparation of students as leaders in a wide range of professions. A growing number of innovative teaching and research initiatives span all Tufts campuses, and collaboration among the faculty and students in the undergraduate, graduate and professional programs across the university's schools is widely encouraged.
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ZenMaster

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President-Elect Obama: Importance of Science Policy at the White House

Former presidential advisors highlight the need for a swift appointment of science advisor
Friday, 05 December 2008

Science, technology and innovation are key elements in addressing the economy, health care, energy and a host of other challenges our nation will face in the coming years.

Because of the importance of science and technology in our society, a new article, Making a Critical Connection: Science Advice and the Next President, highlights the need for the swift appointment of a science advisor whom President-elect Barack Obama trusts. The article is published by the Foresight & Governance Project at the Woodrow Wilson International Center for Scholars and authored by four living presidential science advisors, Democrats Drs. John H. Gibbons and Neal F. Lane and Republicans Drs. Edward E. David and John. P. McTague.

The benefits of making the right decisions regarding science and technology policy are enormous—as are the costs of making mistakes. Over the past 60 years, every president has had a science advisor and, since 1976, an office focused on science and technology issues. The science advisor and the Office of Science and Technology Policy (OSTP) have historically played a central role — usually behind the scenes — in crafting national policies. A robust OSTP, located in the White House complex and closely integrated with the other White House functions such as the Office of Management and Budget, is of great importance.

The Foresight and Governance Project works to improve foresight and long-term planning in the public sector and to help business, government, and the public better understand the impacts and implications of technological change.
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ZenMaster

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Thursday, 4 December 2008

Broccoli Chemical Targets Key Enzyme in Late-stage Cancer

Discovery of target enzyme will aid design of better anti-cancer drugs
Thursday, 04 December 2008

An anti-cancer compound found in broccoli and cabbage works by lowering the activity of an enzyme associated with rapidly advancing breast cancer, according to a University of California, Berkeley, study appearing this week in the online early edition of the journal Proceedings of the National Academy of Sciences.

The compound, indole-3-carbinol, is already undergoing clinical trials in humans because it was found to stop the growth of breast and prostate cancer cells in mice.

The new findings are the first to explain how indole-3-carbinol (I3C) stops cell growth, and thus provide the basis for designing improved versions of the chemical that would be more effective as a drug and could work against a broader range of breast as well as prostate tumours.

"I think one of the real uses of this compound and its derivatives is combining it with other kinds of therapies, such as tamoxifen for breast cancer and anti-androgens for prostate cancer," said co-author Gary Firestone, UC Berkeley professor of molecular and cell biology.

"Humans have co-evolved with cruciferous vegetables like broccoli and Brussels sprouts, so this natural source has a lot fewer side effects."

"This is a major breakthrough in trying to understand what the specific targets of these natural products are," said co-author Leonard Bjeldanes, UC Berkeley professor of toxicology.

"The field is awash with different results in various cells, but no real identification of a specific molecular target for these substances. The beauty of identifying the target like this is that it suggests further studies that could augment the activity of this type of molecule and really specify uses for specific cancers."

Firestone, Bjeldanes and their colleagues showed that I3C inhibits the enzyme elastase, which at high levels in breast cancer cells heralds a poor prognosis: decreased response to chemotherapy, reduced response to endocrine treatment and reduced survival rates.

Elastase is an enzyme that shortens a cellular chemical, cyclin E, which is involved in controlling the cell cycle. The shortened version of cyclin E accelerates the cell cycle, making cancer cells proliferate faster. Firestone showed that I3C prevents the elastase shortening of cyclin E, thereby arresting development of breast cancer cells.

For more than 15 years, Firestone, Bjeldanes and their colleagues have studied the anti-cancer benefits of vegetables in the cabbage family that are lumped together in the genus Brassica and, because of their cross-shaped flowers, are often referred to as cruciferous vegetables.

Though the anti-cancer benefits have been recognized since the 1970s, the mechanism is only now being discovered, in part through the work of Firestone, Bjeldanes and their UC Berkeley colleagues.

"We have connected the dots on one extremely important pathway" by which indole-3-carbinol works, Firestone said.

In previous work, they found that indole-3-carbinol interferes with more than cell proliferation. It also disrupts the migration and alters adhesion properties of cancer cells, as well as counteracts the survival ability of cancer cells, all of which are implicated in cancer cell growth. To have such broad downstream effects, I3C must act at the beginning of a major cellular pathway, Firestone said. The newly reported research pins this activity to elastase and its effect on cyclin E.

Bjeldanes noted that I3C is available as a supplement and is a preferred preventative treatment for recurrent respiratory papillomatosis, a condition involving non-malignant tumours of the larynx. Improved versions of the chemical could thus help treat cancers other than those of the breast and prostate.

Graduate student Ida Aronchik and recent Ph.D. recipient Hanh H. Nguyen, along with colleagues in the Firestone and Bjeldanes labs, have already chemically modified I3C and boosted its activity in cell culture by at least a factor of 100. The lab teams currently are probing the elastase structure and how I3C interacts with it to identify the best parts of the I3C molecule to modify.

I3C is only one of many plant-derived chemicals, called phytochemicals, which Firestone is investigating in his laboratory as potential anti-cancer agents. Among them is the anti-malarial drug artemisinin. Last month, the Journal of Biological Chemistry accepted a paper by Firestone and his colleagues showing that artemisinin blocks prostate cancer cell growth by interfering with the same intracellular pathway, as does I3C. This pathway involves the transcription factor SP1, which latches onto other genes to boost their activity.

"SP1 could be a generalized target of phytochemicals," Firestone said.

"Phytochemicals work because they interact with and inhibit enzymes that control a host of cellular processes, including migration and adhesion."
.........

ZenMaster

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ISSCR: New Guidelines for Stem Cell Therapies

Regulation needed as new study reveals clinics exaggerate claims and omit risks
Thursday, 04 December 2008

Today, the International Society for Stem Cell Research (ISSCR), the world's leading professional organization of stem cell researchers, released new guidelines for the responsible development of safe and effective stem cell therapies for patients. Cell Press will publish a Commentary article that summarizes the Guidelines for the Clinical Translation of Stem Cells, in the December issue of Cell Stem Cell, the official affiliated journal of the ISSCR.

These guidelines define a roadmap for medical researchers and doctors, outlining what needs to be accomplished to move stem cells from promising research to proven treatments for patients. The new guidelines will accelerate the translation of stem cell research into practice while addressing associated scientific, clinical, regulatory, ethical and social issues. Founded on core principles of scientific rigor and ethical conduct, the recommendations offered in the guidelines include an insistence on expert evaluation and independent oversight, a thorough informed consent process to provide patients with essential information on the unique aspects of stem cell-based treatments, and transparency in reporting of clinical trial results.

"Our guidelines will arm patients and their doctors with the information they need to make decisions about whether to seek stem cell treatments," said Dr. Olle Lindvall, co-chair of the ISSCR task force that developed the guidelines and professor in clinical neurology at the University of Lund.

"Stem cell research holds tremendous promise for the development of novel therapies for many serious diseases. However, as clinicians and scientists, we recognize an urgent need to address the problem of unproven stem cell treatments being marketed directly to patients."

Too often rogue clinics around the world exploit patients' hopes by offering unproven stem cell therapies, typically for large sums of money and without credible scientific rationale, oversight or patient protections.

This concern is further emphasized in a Correspondence article from Dr. Timothy Caulfield and colleagues of the University of Alberta, Canada, which also appears in the December issue of Cell Stem Cell. A content analysis of claims made on 19 Web sites offering so-called "stem cell therapies" was performed to assess the portrayal of the services offered by each organization. In addition, the authors assessed whether these claims are substantiated by research reported in the professional medical literature. The authors provide clear evidence that the vast majority of the clinics examined over-promise results and gravely underestimate the potential risks of their offered treatments.

The ISSCR's new guidelines establish standards that can be used to judge the claims made by stem cell clinics and whether the treatments they offer are being developed responsibly. The ISSCR also offers a handbook for patients and their doctors evaluating a stem cell therapy.

The ISSCR urges governments and regulatory bodies to enact the recommendations outlined in these guidelines. The guidelines call for countries without an official regulatory body to develop a way to monitor new stem cell-based treatments, and the ISSCR has offered to advise agencies that want to build these regulatory capacities.

"Regulators have a responsibility to prevent exploitation of patients in their jurisdictions, and where necessary, to close fraudulent clinics and take disciplinary action against the doctors involved," said Dr. George Q. Daley, immediate past-president of the ISSCR and associate director of the Stem Cell Program at Children's Hospital Boston.

To develop these new guidelines, the ISSCR convened an international task force of experts in stem cell science, clinical research and bioethics from 13 countries. Dr. Lindvall and Dr. Insoo Hyun, ISSCR member and professor at Case Western Reserve University, led the task force.

"Our task force has captured the most current, comprehensive thinking on translational stem cell research. The result – these new guidelines – will be valuable for all members of the stem cell community," said Dr. Fiona Watt, president of the ISSCR.

About The International Society for Stem Cell Research:
The International Society for Stem Cell Research (ISSCR) is an independent, non-profit membership organization established to promote and foster the exchange and dissemination of information and ideas relating to stem cells, to encourage the general field of research involving stem cells and to promote professional and public education in all areas of stem cell research and application.

Patients, medical researchers, regulators and those interested should visit the ISSCR's Web site to see the Guidelines, a handbook for patients and more information on stem cell research. In addition, the content of the Guidelines is digested in the Commentary article authored by the task force, which is available online at www.cellstemcell.com/.

References:
New ISSCR Guidelines Underscore Major Principles for Responsible Translational Stem Cell Research
Insoo Hyun, Olle Lindvall, Lars Ährlund-Richter, Elena Cattaneo, Marina Cavazzana-Calvo, Giulio Cossu, Michele De Luca, Ira J. Fox, Claude Gerstle, Robert A. Goldstein, Göran Hermerén, Katherine A. High, Hyun Ok Kim, Hin Peng Lee, Ephrat Levy-Lahad, Lingsong Li, Bernard Lo, Daniel R. Marshak, Angela McNab, Megan Munsie, Hiromitsu Nakauchi, Mahendra Rao, Heather M. Rooke, Carlos Simon Valles, Alok Srivastava, Jeremy Sugarman, Patrick L. Taylor, Anna Veiga, Adrianne L. Wong, Laurie Zoloth, George Q. Daley
Cell Stem Cell, Volume 3, Issue 6, 607-609, 4 December 2008, doi:10.1016/j.stem.2008.11.009

Stem Cell Clinics Online: The Direct-to-Consumer Portrayal of Stem Cell Medicine
Darren Lau, Ubaka Ogbogu, Benjamin Taylor, Tania Stafinski, Devidas Menon, Timothy Caulfield
Cell Stem Cell, Volume 3, Issue 6, 591-594, 4 December 2008, doi:10.1016/j.stem.2008.11.001
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ZenMaster

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Wednesday, 3 December 2008

ALS Model from Human ESCs II

A novel human stem cell-based model of ALS opens doors for rapid drug screening
Wednesday, 03 December 2008

Long thought of as mere bystanders, astrocytes are crucial for the survival and well-being of motor neurons, which control voluntary muscle movements. In fact, defective astrocytes can lay waste to motor neurons and are the main suspects in the muscle-wasting disease amyotrophic lateral sclerosis (ALS).

To get to the root of this complicated relationship, researchers from the Salk Institute for Biological Studies for the very first time established a human embryonic stem cell (hESC)-based system for modelling ALS. Their study confirmed that dysfunctional human astrocytes turn against their charges and kill off healthy motor neurons. But more importantly, treating the cultured cells with apocynin, a powerful anti-oxidant, staved off motor neuron death caused by malfunctioning astrocytes.

Their findings, which appear in the Dec. 4 issue of the journal Cell Stem Cell, provide new insight into the toxic pathways that contribute to the demise of motor neurons in ALS and open up new possibilities for drug-screening experiments using human ALS in vitro models, as well as clinical interventions using astrocyte-based cell therapies.

"A variety of drugs that had demonstrated significant efficacy in mouse models didn't keep their promise in both preclinical and clinical trials," says Fred H. Gage, Ph.D., a professor in the Laboratory for Genetics, who led the study. In fact, just one drug — riluzole — has been approved by the FDA to treat ALS, and it only slows the course of the disease by two months.

"There is an urgent need for new ALS models that have the potential to translate into clinical trials and that could, at a minimum, be used in conjunction with the murine models to verify drugs and drug targets," says Gage.

ALS, also known as Lou Gehrig's disease, was named after the legendary New York Yankee slugger who lent his name to the mysterious illness over 60 years ago. Usually fatal, the neurodegenerative disease attacks motor neurons controlling voluntary movement, leading to progressive paralysis and muscle atrophy.

Although ALS was first classified as a disease over 140 years ago, there are still few clues as to its cause. An important step toward understanding the disease came when scientists discovered that ALS can be induced by inherited mutations in the gene encoding the SOD1 enzyme, short for superoxide dismutase 1. This enzyme protects the body from damage caused by free radicals, highly reactive molecules produced by cells during normal metabolism.

Spinal motor neurons express high levels of SOD1, which many originally thought might explain their selective vulnerability. But soon, mouse experiments revealed that motor neuron degeneration is not necessarily associated with the expression of defective SOD1 in the motor neurons per se but rather with its expression in a critical number of neighbouring support cells.

Since most treatments that worked in ALS mouse models did not live up to expectations in preclinical and clinical trials, postdoctoral researcher and first author M. Carol Marchetto, Ph.D., looked for an alternative.

"Transgenic mice containing the human mutated forms of SOD1 have been very useful to study the disease onset and progression. But we felt that cell culture models using both human neurons and astrocytes could potentially be very useful for drug screening and, to some extent, cell replacement therapies."

To uncover the contribution of astrocytes to human motor neuron degeneration, Marchetto first coaxed hESCs to differentiate into motor neurons through a series of physical manipulations and exposure to a number of growth factors. When she co-cultured these cells with human astrocytes expressing a mutated form of SOD1, the number of motor neurons alive in the Petri dish plummeted.

"In the presence of the mutation, the astrocytes activated an inflammatory response and started producing reactive oxygen species, a hallmark of ALS," says Marchetto.

Top: When motor neurons (shown in red) are grown in the presence of defective astrocytes their numbers plummet. Bottom: Treating the cultures with apocynin, a powerful anti-oxidant, dramatically increases the survival of motor neurons. All cells' nuclei are labelled blue and neurons are shown in green. Right panel: Only motor neurons are shown. Credit: Courtesy of Dr. M. Carol Marchetto, Salk Institute for Biological Studies.

When she treated these cells with known antioxidants such as apocynin, which is found in many plants, epicatechin, one of the beneficial ingredients in green tea and chocolate, or alpha-lipoic acid, which is produced by the body, the percentage of astrocytes churning out harmful reactive oxygen species decreased significantly. Not only that, when she treated motor neurons cultured in the presence of mutant astrocytes, apocynin — the only one tested in a co-culture experiment — helped motor neurons withstand their no-longer-supportive environment.

"We believe that we can use this system as a rapid drug screening test for oxidative damage to identify the best candidates for subsequent long-term co-culture experiments," says Marchetto.

While research on the effects of the SOD1 gene mutation is providing important clues about the possible causes of motor neuron death, only a small fraction of all ALS cases are actually due to the mutation; other as yet unidentified genetic causes clearly exist.

"The rapid advances in induced pluripotent stem cell technology will soon allow us to generate patient-specific stem cells that can be used in our co-culture assay to gain new insight into the different causes of ALS," says Gage.

This study was funded by Project ALS, the Dana and Christopher Reeve Foundation, the California Institute for Regenerative Medicine, the Lookout Fund, and the National Institutes of Health.

Reference:
Non-Cell-Autonomous Effect of Human SOD1G37R Astrocytes on Motor Neurons Derived from Human Embryonic Stem Cells
Maria C.N. Marchetto, Alysson R. Muotri, Yangling Mu, Alan M. Smith, Gabriela G. Cezar and Fred H. Gage
Cell Stem Cell, Volume 3, Issue 6, 649-657, 4 December 2008

See also:
ALS Model from Human ESCs I
Motor neurons derived from human embryonic stem cells provide insight into ALS
CellNEWS - Wednesday, 03 December 2008
.........

ZenMaster

For more on stem cells and cloning, go to CellNEWS at
http://cellnews-blog.blogspot.com/ and
http://www.geocities.com/giantfideli/index.html

ALS Model from Human ESCs I

Motor neurons derived from human embryonic stem cells provide insight into ALS
Wednesday, 03 December 2008

Two new research studies use motor neurons derived from human embryonic stem cells (hESCs) to demonstrate that multiple toxic pathways contribute to the devastating degeneration associated with Amyotrophic Lateral Sclerosis (ALS) and that protective therapeutics will need to oppose the disease on multiple fronts. The separate studies, published by Cell Press in the December issue of the journal Cell Stem Cell, also underscore the validity of using human stem cells to both identify new strategies for protecting motor neurons and screen potential therapeutics.

ALS, also known as Lou Gehrig's disease, is characterized by death of motor neurons in the brain and spinal cord, muscle atrophy and fatal paralysis. Previous research has shown that mutations in the widely expressed enzyme superoxide dismutase I gene (SOD1) can lead to ALS. Work with animal models expressing mutant SOD1 has provided valuable insight into the complex metabolic pathways involved in disease pathogenesis and has indicated that non-neuronal support cells, called astrocytes, contribute to disease progression.

However, drugs that have successfully protected motor neurons in mouse models have not proven useful in human clinical trials.

"There is an urgent need for new ALS models that have the potential to be translated into clinical trials that could, at a minimum, be used in conjunction with mouse models to verify targets and drugs," explains Dr. Fred H. Gage from The Salk Institute for Biological Studies.

To investigate the contribution of astrocytes to human motor neuron degeneration, Dr. Gage and colleague Dr. Corol Marchetto co-cultured hESC-derived motor neurons with human primary astrocytes expressing mutated SOD1. They found that the conditions were selectively toxic for the healthy motor neurons. The toxicity was related to an inflammatory response initiated by the astrocytes and the production of damaging reactive oxygen species (ROS). Importantly, pharmacological blockade of ROS production rescued the motor neurons from mutant SOD1 toxicity.

A separate study led by Dr. Kevin C. Eggan and colleague Paolo Di Giorgio from The Harvard Stem Cell Institute also used hESC-derived motor neurons to examine the toxic effects of astrocytes expressing mutant SOD1.

"We examined the utility of specific neuronal subtypes, including spinal motor neurons, derived from hESCs for investigating the disease mechanisms leading to ALS and the identification of small molecules that can counteract their effects," says Dr. Eggan.

Using a sophisticated genetic screening technique, the researchers identified specific genes that were expressed in the mutant astrocytes. One molecule, prostaglandin D2, could by itself induce a loss of motor neurons similar to that seen in co-culture with SOD1 mutant astrocytes. The group went on to show that blockade of the prostaglandin D2 receptor rescued motor neurons from the astrocyte-induced toxicity.

The findings of both studies confirm the toxic interactions between mutant SOD1-expressing astrocytes and motor neuron as a valid target for development and testing of ALS therapeutics. Further, the research shows that hESC-based systems are an invaluable research tool for disease modelling with specific cell types.

References:
Human Embryonic Stem Cell-Derived Motor Neurons Are Sensitive to the Toxic Effect of Glial Cells Carrying an ALS-Causing Mutation
Francesco Paolo Di Giorgio, Gabriella L. Boulting, Samuel Bobrowicz and Kevin C. Eggan
Cell Stem Cell, Volume 3, Issue 6, 637-648, 4 December 2008

Non-Cell-Autonomous Effect of Human SOD1G37R Astrocytes on Motor Neurons Derived from Human Embryonic Stem Cells
Maria C.N. Marchetto, Alysson R. Muotri, Yangling Mu, Alan M. Smith, Gabriela G. Cezar and Fred H. Gage
Cell Stem Cell, Volume 3, Issue 6, 649-657, 4 December 2008

See also:
ALS Model from Human ESCs II
A novel human stem cell-based model of ALS opens doors for rapid drug screening
CellNEWS - Wednesday, 03 December 2008
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ZenMaster

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