20090707-4

Master Heart Cells 

Harvard discovery gives new tools for drug development

GoogleNews.com, Boston Globe, July 3, 2009, by Carolyn Y. Johnson  —  Harvard University scientists said yesterday they discovered a master human heart cell that gives rise to three major types of heart tissue, providing new tools for drug development and an important advance toward the ultimate goal of repairing damaged hearts.

Using human embryonic stem cells, the researchers have unraveled part of the process by which the human heart is built during development – insight they hope could be used to understand congenital heart disease and create new therapies for cardiovascular disease, the top cause of death in the United States.

“Since these [cells] are entirely human, you can use this system now to study the role of specific genes in human heart disease, and as ways to screen drugs for cardiotoxicity and for therapeutic effect,” said Dr. Kenneth R. Chien, director of the Cardiovascular Research Center at Massachusetts General Hospital and principal faculty member at the Harvard Stem Cell Institute. He is senior author of the paper, published in Nature yesterday.

The work points to new applications for regenerative medicine. For years, attempts to repair damaged heart tissue using different types of cells have come back with “ambiguous, disappointing, marginal, and, in certain cases, negative” results, Chien said. For example, Genzyme Corp. of Cambridge stopped enrolling patients in a clinical trial for a heart cell therapy three years ago because it was deemed to have little chance of success.

Because the new work reveals progenitor cells that naturally create specific types of heart tissue during development, Chien thinks they might have a better chance of repairing damaged hearts.

But the greatest near-term promise of the work might be in routine drug development. It could now be possible, for example, to create large numbers of heart muscle cells to test drugs.

“Add one drug, two drugs, or all combinations of drugs a heart patient would take” to test how effective or toxic compounds are in actual human heart cells, said Christine Mummery, a professor of developmental biology at Leiden University Medical Center who was not involved with the work. “It’s really a kind of tool to bring us a step further.”

Drug companies are especially interested in such applications. Using the actual human cells affected by a disease, instead of mice, dogs, or other stand-ins, could potentially speed up drug development by giving com panies a more accurate template for screening potential drugs. Animal cells and other types of assays have been invaluable for testing and screening drugs, but the new cells could give scientists a chance to see how the human cells they are interested in react to drugs.

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The human heart develops from patches of early heart stem cells, which tend to congregate in areas linked with congenital heart disease, including the heart valves and pumping chambers. — ST ILLUSTRATIO

Such cells could also prevent companies from spending too much time on a drug that ultimately fails. One big concern at pharmaceutical companies is that drugs might have a side effect on the heart that only emerges late in the drug development process, said John D. McNeish, executive director of Pfizer Regenerative Medicine. Testing the drug on human heart cells might alert scientists to side effects before they begin administering the drug to patients in clinical trials.

“I think this is in many ways a groundbreaking work,” McNeish said, because of both its short- and long-term implications. “It is fair to say in the future, stem cell technology could develop highly predictive cell-based assays for cardiotoxicity that could one day replace” the current models, such as using cells from cadavers or animals.

GlaxoSmithKline, the pharmaceutical company that made a $25 million investment in the Harvard Stem Cell Institute last year, is interested in using stem cells as drug discovery tools.

“Stem cells would allow pharmaceutical researchers to see the effects of new compounds on human cells, and so ultimately replace current testing on non-human cells, and help improve the accuracy of screening to improve therapeutic efficacy and reduce risks to patients,” Aaron Chuang, scientific manager for stem cell research at GSK, wrote in an e-mail.

Chien and his colleagues began their work by searching in fetal human hearts for master cells, grandfather cells that give rise to three major types of tissue.

His team confirmed the presence of master cells in fetal hearts, but found that they decrease in number as the heart develops. They turned to human embryonic stem cells to better understand the cells and their potential applications.

Using stem cells, which are capable of turning into any cell in the human body, they created the master stem cells. Then, they tagged those cells, and confirmed that the master cells gave rise to three types of cells. They also identified a family of “intermediate” cells, each of which is a mother to a single kind of tissue – giving rise to heart muscle tissue, smooth muscle tissue that contracts to regulate blood flow, or endothelial cells that line blood vessel walls.

Chien is already pushing the work forward. Plans include turning back the clock of adult cells to create embryonic-like stem cells that could create cardiac master cells. A major question is whether such cells would be equivalent to the ones made from embryonic stem cells. If it works, that could offer the possibility of creating patient-specific cells to model different diseases. Chien is also interested in understanding the role progenitor cells play in congenital heart disease.

But ultimately, he wants to use the basic understanding of the cell to treat heart disease.

“My interest,” Chien said, “is taking the disease out.”

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A color enhanced MRI image of the brain shows one of the theories into what may be the chemical basis for Schizophrenia. Researchers have found reduced receptors for dopamine in the brain (areas colored) Credit: Neil Borden/ Science Photo Library 

Scientific breakthrough offers hope of new treatments for mental condition

GoogleNews.com, Independent.co.uk, July 3, 2009, by Steve Connor  —  Scientists have discovered a remarkable similarity between the genetic faults behind both schizophrenia and manic depression in a breakthrough that is expected to open the way to new treatments for two of the most common mental illnesses, affecting millions of people.

Previously doctors had assumed that the two conditions were quite separate. But new research shows for the first time that both have a common genetic basis that leads people to develop one or other of the two illnesses.

Three different international studies investigated the genetic basis of schizophrenia by pooling their analysis of about 15,000 patients and nearly 50,000 healthy subjects to find that thousands of tiny genetic mutations – known as single nucleotide polymorphisms (SNPs) – are operating in raising the risk of developing the illness.

Each mutation on its own increased the risk of developing schizophrenia by about 0.2 per cent but collectively they were found to account for at least a third of the total risk of developing schizophrenia. The condition is known to have a strong inherited component, accounting for about 80 per cent of the total risk, but it is also influenced by upbringing and environment.

However, one of the most surprising findings to emerge from the three studies was that the same array of genetic variations in SNPs was also linked with bipolar disorder, a discovery that is at odds with the orthodoxy in psychiatry stating that the two conditions are clinically distinct, the scientists said. The findings are a milestone in the understanding of both schizophrenia and manic depression – also known as bipolar disorder – which could eventually lead to new ways of either preventing or treating conditions that cause untold human misery and cost the NHS hundreds of millions of pounds each year.

“If some of the same genetic risks underlie schizophrenia and bipolar disorder, perhaps these disorders originate from some common vulnerability in brain development,” said Thomas Insel, director of the US National Institute for Mental Health in Bethesda, Maryland, which part-funded the studies. “Of course the big question then is how some people develop schizophrenia and others develop bipolar disorder.”

Although the schizophrenia studies have so far only identified a handful of the many thousands of genetic variations implicated in the mental illness, scientists believe it represents a breakthrough that will accelerate the understanding of the condition and the development of new drugs and treatments. “This is a pretty major breakthrough for us because before today you could count on the thumb of one hand the number of common [genetic] variants that have been reliably identified for schizophrenia,” said Michael O’Donovan, professor of psychiatric genetics at the Medical Research Council’s neurogenetics center in Cardiff.

“However, what we’ve found so far explains only a tiny fraction of the total risk of schizophrenia. Some of us were surprised to find that not only did these genes contribute to schizophrenia but they also contribute to bipolar disorder. So that really suggests that the two disorders are not really as distinct as we thought in psychiatry.”

The three studies, published in the journal Nature, have been possible because of technical advances in the analysis of the genomes of patients, enabling scientists to rifle through vast amounts of DNA in order to make comparisons between patients and healthy “controls”.

Eric Lander, the founding director of the Broad Institute, one of the 11 research centers of the consortium formed from laboratories in the United States, Europe and Australia, which were behind the studies, and a member of Barack Obama’s Council of Advisers on Science and Technology, said that the pace of research into schizophrenia was accelerating fast. “Over the past year, using techniques designed to study common DNA changes, psychiatric disease geneticists have detected more statistically compelling findings than in the previous 100 years,” he said.

Some of the genetic variations associated with schizophrenia appear to occur within a region of the genome known to be involved in controlling the immune system. This might help to explain why babies born in winter and spring when influenza is rife, or to women who have had flu during pregnancy, are at slightly increased risk of developing schizophrenia in later life, the scientists said.

“Discoveries such as these are crucial for teasing out the biology of the disease and making it possible for us to begin to develop drugs targeting the underlying causes and not just the symptoms of the disease,” said Kari Stefansson, the head of deCode Genetics, the Icelandic company involved in one of the three studies. “One of the reasons this study was so successful is its unprecedented size. Pooling our resources has yielded spectacular results, which is what the participants from three continents hoped for.”

The study also found links to schizophrenia with DNA variations in certain genes involved in the growth of nerve cells in the brain and the production of a protein messenger molecule that helps the transmission of signals from one brain cell to another.

Schizophrenia affects one in 100 people at some time in their life. It is a chronic, long-term illness resulting in persistent delusions and hallucinations and is estimated to cost the taxpayer about £2bn a year in care and treatment. The costs to society at large – from the families of affected patients to the money spent by the criminal justice system – are thought to be at least twice as high.

Professor David St Clair, chair of mental health at the University of Aberdeen, said the global drugs bill alone for schizophrenia is £12.5bn, not to mention other huge costs such as hospital stays, lost employment and diminished quality of life. “Our findings are a real scientific breakthrough since they tell us a lot more about the nature of the genetic risk of schizophrenia than we knew as little as a year ago,” he said.

“However, this is not a breakthrough that is going to change clinical practice any time soon. It will still be many years before our findings can be translated into new drug treatments. Much more work is also still required for us to piece together the overall genetic architecture of schizophrenia.”

Curses of the mind

Schizophrenia

Schizophrenia is a severe, chronic brain disorder that usually strikes in late adolescence or early adulthood and is marked by hallucinations and delusions. Sufferers may hear voices or believe that other people are controlling them or reading their minds. Such experiences can be terrifying and can cause fearfulness, withdrawal or extreme agitation. People with schizophrenia have reduced brain receptors for the dopamine messenger. They may not make sense when they talk, or they can appear to be perfectly fine and normal until they are asked what they are really thinking. Treatments can be effective, but most people have some residual symptoms that can stay with them for life.

Bipolar disorder

Bipolar disorder, or manic depression, is marked by unusual shifts in mood, energy, activity levels and the ability to carry out day-to-day tasks. Like schizophrenia, bipolar disorder often manifests itself in late adolescence or early adulthood, although it may not be diagnosed for many years. The ups and downs are different from the normal ones that everyone experiences and they can result in damaged relationships, poor performances in school and jobs and even suicide. Sometimes a person with severe episodes of mania or depresssion has psychotic symptoms such as hallucinations or delusions, such as believing that he or she is famous or has lots of money.

University of California – Los Angeles (2009, July 6). Immune System Linked To Schizophrenia. ScienceDaily  –  Schizophrenia is a devastating mental disease, thought to be caused by the interaction of both genetic and environmental factors. Because there is no biochemical test that can identify the disorder, physicians rely upon the recognition of its symptoms – which can include auditory hallucinations and paranoia – in order to make their diagnosis.

Now following on their earlier work that identified three gene locations that may be implicated in schizophrenia, researchers at UCLA and colleagues from around the world have, for the first time, identified additional genes that confirm what scientists have long suspected – that the immune system may play a role in the development of the disorder. Further, they have also identified genetic anomalies that disrupt the cellular pathways involved in brain development, memory and cognition, all markers of schizophrenia.

The research appears in the July 1 online edition of the journal Nature.

Roel Ophoff, the co-lead author and an assistant professor at the Center for Neurobehavioral Genetics at the UCLA Semel Institute for Neuroscience and Human Behavior, and his collaborators from nearly 50 institutions worldwide, performed a genome-wide scan of 2,663 people diagnosed with schizophrenia and 13,498 controls from eight European locations. They were looking for single nucleotide polymorphisms (SNP), genetic variations that are commonly present in the general population but more often present in those suffering from the disorder. In total, nearly 314,000 SNPs were included in their analysis.

They found significant associations with genetic markers on the Major Histocompatibility Complex (MHC), a group of genes that controls several aspects of the immune response. Further, they discovered additional variations in two other genes, called NRGN and TCF4, which points to perturbation of pathways involved in brain development, memory and cognition.

“This is another step forward in understanding the biological basis of this disorder, one that robs people of their lives,” said Ophoff, who holds a joint appointment at the University of Utrecht, The Netherlands. “It also shows the importance of worldwide collaborations for the study of schizophrenia genetics, because it allows us to do very large numbers of scans.”

The findings are significant yet not without challenge, said Ophoff, since the study aimed at the “common variants” in the human genome. “In other words,” he said, “these are not rare mutations present in only a few individuals, but these genetic variants are abundantly present in the population. Anybody could carry this variant, but that doesn’t mean they will necessarily develop the disease. Yet, when you look at the population at large, these variants are more often present in patients than in healthy control subjects.”

And that’s important, he noted, in developing new techniques to thwart the disease. “Knowing these specific genes are involved in the pathway leading to schizophrenia provides unique clues as to which molecular mechanisms are involved,” he said.

While the association between schizophrenia and the immune system has long been suspected, the evidence for it has, until now, been mostly circumstantial. And impaired cognitive and memory functions are increasingly being recognized as core features of schizophrenia, which are poorly addressed by current medications.

“The three common genetic variants we describe, then, which we feel predisposes certain individuals to schizophrenia, have the potential to be translated into targets for the development of new and novel medications,” Ophoff said.

Some 40 other authors and institutions contributed to the paper, and there were multiple funding sources; for UCLA, funding was provided by the National Institute of Mental Health. Other UCLA authors included Dr. Nelson Freimer, director of the Center for Neurobehavioral Genetics and professor of psychiatry, and Rita Cantor, professor of human genetics, both members of the David Geffen School of Medicine. The UCLA authors report no conflicts of interest.


Journal reference:

  • 1. Stefansson H, et al. Common variants conferring risk of schizophrenia. Nature, July 1, 2009 DOI: 10.1038/nature08186

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Physorg.com, June/July 2009  —  Long-term memory formation in honeybees is instigated by a calcium ion cascade. Researchers writing in the open access journal BMC Biology have shown that calcium acts as a switch between short- and long-term storage of learned information. 

Jean-Christophe Sandoz led a team of researchers from the CNRS, the Université de Toulouse and the French Calcium Research Network, who carried out the neurological honeybee experiments. He said, “By modulating the intracellular calcium concentration in the insects’ brains, we’ve been able to demonstrate that, during olfactory conditioning, Ca2+ is both a necessary and a sufficient signal for the formation of protein-dependent long-term memory”.

Sandoz and his colleagues studied a learned behaviour in the bees, extension of the proboscis in response to olfactory stimuli associated with food. Three days after decreasing calcium levels during learning, the bees stopped responding to the odor, and three days after increasing calcium during learning, bees’ response to the odor were stronger. In addition, the researchers found that the increased memory performance in bees induced by increased calcium depended on protein synthesis. According to Sandoz, “We have found here that the modulation of calcium during learning affects long-term memory specifically while leaving learning and short-term memory intact”.

Source: BioMed Central

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Bacteriology professor Cameron Currie maintains an Acromyrmex volcanus colony in his UW-Madison laboratory. The ants are located on a spongy fungus garden, which they grow themselves. Photo: B W Hoffmann

PhysOrg.com, June/July 2009, by Margaret Broeren  —  Nestled within the twisting fungus gardens of leaf-cutter ants exists a complex symbiotic web that has evolved over millions of years. Now, with the help of a major genomic sequencing grant from Roche Applied Science, scientists at the University of Wisconsin-Madison will be able to analyze these interactions at the molecular scale.

“By sequencing genomes of all the major players, we can study the evolution of the system,” says Cameron Currie, a UW-Madison bacteriology professor and one of the project’s lead researchers. “It would be one of the first, if not the first, genomic level study of a community of organisms over evolutionary time.”

As winners of Roche Applied Science’s 10 Gigabase Grant Program, UW-Madison and Great Lakes Bioenergy Research Center (GLBRC) scientists Currie, Steven Slater and Garret Suen will be part of a team that will use Roche technology to sequence the known members of the ant-fungus symbiosis, which includes three ant genomes and 14 ant-associated fungal and bacterial genomes.

“Three sequenced ant genomes will be truly spectacular,” says Ted Schultz, a research entomologist at the Smithsonian Institution National Museum of Natural History. “This is going to advance the field a quantum level beyond what is done now.

“The fungus-growing ant system is already a model system for studying symbiosis and coevolution,” says Schultz. “This project will solidify its status as the premier model system for those kinds of studies.” 

Most of the DNA samples to be sequenced will come from Currie’s UW-Madison lab, which is also investigating how the leaf-cutter ants break down large amounts of cellulose as part of their work with the GLBRC. 

Sequencing data will be generated by the end of the summer, but finalizing the genome sequences and annotation will be an ongoing project that will span a number of years, says Slater, GLBRC scientific programs manager and an investigator on the project.

To tackle a project of this size and scope, the research team is looking for extra help in a very interesting place: high school and undergraduate classrooms. By recruiting university faculty and training high school teachers, then providing well-stocked research kits and the support of a dedicated Ph.D.-level scientist, students will have the opportunity to perform novel research and make a contribution to functional gene analysis.

“Any kid who contributes some DNA sequence or functionally tests a gene prediction has truly added to the scientific effort. For example, closing [sequence] gaps is expensive and time-consuming, but it’s an important part of genomics and can be a wonderful education tool,” says Slater. “Kids learn basic molecular biology and learn to understand genome sequencing and genome assembly if they’re tasked with closing those gaps. Our hope is that this becomes a nucleus for a much larger national program – a way of teaching science that’s participatory.”

  The Joint Genome Institute, another Department of Energy laboratory, will be assisting with both sequence analysis and educational efforts.

As genomic data is collected and annotated, researchers will have unprecedented potential to study ecology, evolution, behavior and development in a 50-million-year association. 

“This provides us a unique look under the hood of some very important ecosystems,” says Tim Donohue, GLBRC director and UW-Madison bacteriology professor. “These ants and their partner microbes have evolved over millions of years to digest plant material, including the cellulose in plant cell walls.” 

Some of these ant communities have a picky appetite and only eat certain types of plant leaves; others are omnivores and digest the cellulose in a wide variety of leaves. GLBRC is studying the fungi and bacteria from these communities to identify microbial enzymes that can help generate fuels from the cellulose, or non-edible, part of the leaf.

“The Roche support leverages the expertise that GLBRC has brought to the table and provides us with a unique look at the ant part of this food chain,” says Donohue. “This information will ultimately allow evolutionary biologists to understand how the ants and microbes have adjusted their genetic blueprints to become effective partners in this food chain.” 

The human genome is composed of 3 billion base pairs of DNA, and it took more than a decade to completely sequence. But technology improvements have made DNA sequencing much faster and cheaper. “In terms of total base pairs,” Currie says, “this project is roughly half the scale of the human genome project.” 

With Currie, Nicole Gerardo of Emory University, who works on insect-microbe interactions, will co-lead the research team. The group also includes her Emory colleague James Taylor, a computational biologist focused on analyzing genomic data. George Weinstock, a veteran of insect genome sequencing, and Sandra Clifton, an expert on analyzing microbial genomes, from The Genome Center at Washington University will round out the research team.

Roche Applied Science’s 10 Gigabase Grant Program for DNA sequencing and transcriptome analysis studies awards up to 10 gigabases of DNA or cDNA sequencing data to an individual, institution or corporation.

Roche Applied Science will perform all sequencing, primary data generation and analysis using the Genome Sequencer FLX System, developed by 454 Life Sciences. The 10 gigabases of data will be generated using the new Genome Sequencer FLX reagents that produce an average of 400-base-pair read lengths. In total, up to 25 million sequencing reads will be generated, resulting in 10 gigabases of information. 

The Great Lakes Bioenergy Research Center is one of three Department of Energy Bioenergy Research Centers funded to make transformational breakthroughs that will form the foundation of new cellulosic biofuels technology.

Provided by University of Wisconsin-Madison