For more than 20 years, doctors have been using cells from blood that remains in the placenta and umbilical cord after childbirth to treat a variety of illnesses, from cancer and immune disorders to blood and metabolic diseases.
This microscope image shows a colony of neurons derived from cord-blood cells using stem cell reprogramming technology. The green and red glow indicates that the cells are producing protein makers found in neurons, evidence that the cord-blood cells did in fact morph into neurons. The blue glow marks the nuclei of the neurons. Credit: Image: Courtesy of Alessandra Giorgetti
Now, scientists at the Salk Institute for Biological Studies have found a new way-using a single protein, known as a transcription factor-to convert cord blood (CB) cells into neuron-like cells that may prove valuable for the treatment of a wide range of neurological conditions, including stroke, traumatic brain injury and spinal cord injury.
The researchers demonstrated that these CB cells, which come from the mesoderm, the middle layer of embryonic germ cells, can be switched to ectodermal cells, outer layer cells from which brain, spinal and nerve cells arise. “This study shows for the first time the direct conversion of a pure population of human cord blood cells into cells of neuronal lineage by the forced expression of a single transcription factor,” says Juan Carlos Izpisua Belmonte, a professor in Salk’s Gene Expression Laboratory, who led the research team. The study, a collaboration with Fred H. Gage, a professor in Salk’s Laboratory of Genetics, and his team, was published on July 16 in the Proceedings of the National Academy of Sciences.
"Unlike previous studies, where multiple transcription factors were necessary to convert skin cells into neurons, our method requires only one transcription factor to convert CB cells into functional neurons," says Gage.
The Salk researchers used a retrovirus to introduce Sox2, a transcription factor that acts as a switch in neuronal development, into CB cells. After culturing them in the laboratory, they discovered colonies of cells expressing neuronal markers. Using a variety of tests, they determined that the new cells, called induced neuronal-like cells (iNC), could transmit electrical impulses, signaling that the cells were mature and functional neurons. Additionally, they transferred the Sox2-infused CB cells to a mouse brain and found that they integrated into the existing mouse neuronal network and were capable of transmitting electrical signals like mature functional neurons.
"We also show that the CB-derived neuronal cells can be expanded under certain conditions and still retain the ability to differentiate into more mature neurons both in the lab and in a mouse brain," says Mo Li, a scientist in Belmonte’s lab and a co-first author on the paper with Alessandra Giorgetti, of the Center for Regenerative Medicine, in Barcelona, and Carol Marchetto of Gage’s lab. "Although the cells we developed were not for a specific lineage-for example, motor neurons or mid-brain neurons-we hope to generate clinically relevant neuronal subtypes in the future."
Importantly, says Marchetto, “We could use these cells in the future for modeling neurological diseases such as autism, schizophrenia, Parkinson’s or Alzheimer’s disease.”
Cord blood cells, says Giorgetti, offer a number of advantages over other types of stem cells. First, they are not embryonic stem cells and thus they are not controversial. They are more plastic, or flexible, than adult stem cells from sources like bone marrow, which may make them easier to convert into specific cell lineages. The collection of CB cells is safe and painless and poses no risk to the donor, and they can be stored in blood banks for later use.
"If our protocol is developed into a clinical application, it could aid in future cell-replacement therapies," says Li. "You could search all the cord blood banks in the country to look for a suitable match."
ScienceDaily (July 16, 2012) — A team of scientists at The New York Stem Cell Foundation (NYSCF) Laboratory led by Scott Noggle, PhD, NYSCF-Charles Evans Senior Research Fellow for Alzheimer’s Disease, has developed the first cell-based model of Alzheimer’s disease (AD) by reprogramming skin cells of Alzheimer’s patients to become brain cells that are affected in Alzheimer’s. This will allow researchers to work directly on living brain cells suffering from Alzheimer’s, which until now had not been possible. Andrew Sproul, PhD, a postdoctoral associate in Dr. Noggle’s laboratory, will present this work on July 19 at the Alzheimer’s Association International Conference (AAIC) held in Vancouver.
Dr. Noggle and his team reprogrammed skin cell samples taken from twelve patients diagnosed with early-onset Alzheimer’s and from healthy, genetically related individuals into induced pluripotent stem (iPS) cells, which can differentiate into any cell type. The team of scientists used these iPS cells to create cholinergic basal forebrain neurons, the brain cells that are affected in Alzheimer’s. These cells recapitulate the features and cellular-level functions of patients suffering from Alzheimer’s, a devastating disease that affects millions of people globally but for which there is currently no effective treatment.
NYSCF has pioneered the creation of disease models based on the derivation of human cells. Four years ago, a NYSCF-funded team created a cell-based model for ALS, or motor neuron disease, the first patient-specific stem cells created for any disease. The cell-based model for Alzheimer’s builds on this earlier work.
"Patient derived AD cells will prove invaluable for future research advances, as they already have with patient-derived ALS cells," said NYSCF CEO Susan Solomon. "They will be a critical tool in the drug discovery process, as potential drugs could be tested directly on these cells. Although research on animals has provided valuable insight into AD, we aren’t mice, and animals don’t properly reflect the features of the disease we are trying to cure. As we work to find new drugs and treatments our research should focus on actual human sufferers of Alzheimer’s disease," emphasized Ms. Solomon
This cell-based model has already led to important findings. Preliminary results of this NYSCF research, done in collaboration with Sam Gandy, MD, PhD, an international expert in the pathology of Alzheimer’s at Mount Sinai School of Medicine, demonstrated differences in cellular function in Alzheimer’s patients. Specifically, Alzheimer’s neurons produce more of the toxic form of beta amyloid, the protein fragment that makes up amyloid plaques, than in disease-free neurons.
"iPS cell technology, along with whole genome sequencing, provide our best chance at unravelling the causes of common forms of Alzheimer’s disease," noted Dr. Gandy.
"This collaboration is a great example of how NYSCF is bringing together experts in stem cell technology and clinicians to save and enhance lives by finding better treatments," Ms. Solomon explained.
The research to be reported at the AAIC by Andrew Sproul focused on stem cell models of individuals with presenilin-1 (PSEN1) mutations, a genetic cause of AD. As Dr. Sproul has said, this cell-based model could “revolutionize how we discover drugs to potentially cure Alzheimer’s disease.”
Activity lingers longer in certain areas of the brain in those with Alzheimer’s than it does in healthy people, Mayo Clinic researchers who created a map of the brain found. The results suggest varying brain activity may reduce the risk of Alzheimer’s disease. The study, “Non-stationarity in the “Resting Brain’s” Modular Architecture,” was presented at the Alzheimer’s Association International Conference and recently published in the journal PLoS One.
Researchers compared brain activity to a complex network, with multiple objects sharing information along pathways.
"Our understanding of those objects and pathways is limited," says lead author David T. Jones, M.D. "There are regions in the brain that correspond to those objects, and we are not really clear exactly what those are. We need a good mapping or atlas of those regions that make up the network in the brain, which is part of what we were doing in this study."
Researchers examined 892 cognitively normal people taking part in the Mayo Clinic Study of Aging, and set out to create an active map of their brains while the people were “at rest,” not engaged in a specific task. To do this, they employed task-free, functional magnetic resonance imaging to construct an atlas of 68 functional regions of the brain, which correspond to the cities on the road map.
Researchers filled in the roads between these regions by creating dynamic graphic representations of brain connectivity within a sliding time window.
This analysis revealed that there were many roads that could be used to exchange information in the brain, and the brain uses different roads at different times. The question to answer then, said Dr. Jones, is whether or not Alzheimer’s patients used this map and these roads in a different way than their healthy peers.
"What we found in this study was that Alzheimer’s patients tended to spend more time using some roads and less time using other roads, biasing one over the other," he says.
While more research is needed, the researchers say one implication is that how we use our brains may protect us from Alzheimer’s. Dr. Jones says exercise, education, and social contacts may help balance activity in the brain.
"Diversifying the mental space that you explore may actually decrease your risk for Alzheimer’s," he says.
One of the marvels of brain development is the mass migration of nerve cells to their functional position. European research has investigated the molecules required for their successful navigation.
Credit: Thinkstock
Formation of the cerebral cortex during embryonic development requires the migration of billions of cells from their birth position to their final destination. A motile nerve cell must have internal polarity to move in the specified direction. What is more, neurons then have to extend neurites or projections from the cell body to communicate with each other.
The key to this extraordinary feat of organisation lies in cell signalling pathways. The EU-funded Neuronal Polarity project aimed to characterise these cascades important in cerebral cortex development. At a later stage, defective cortical architecture can be responsible for brain pathologies including microcephaly, epilepsy and schizophrenia.
Project scientists showed that in vivo the guanine triphosphatase GTPase Ras-proximate-1 (Rap 1) caused an accumulation of neurons halfway to their destination. The team used time-lapse video microscopy and immunostaining to show that the problem does not lie with motility of the neurons but in a defect in their polarity. Other evidence from motility tests in vitro and the fact that some neurons do actually make it to their destination, albeit slowly, suggest Rap 1 is important for initial polarisation of the neurons.
The transmembrane receptor N-cadherin (Ncad) also has an important function in polarising cortical neurons. Experimental data confirmed that this receptor is involved downstream from Rap 1. Overall, inhibition of Rap 1 reduces Ncad presence.
Neuronal Polarity scientists suggest that Rap 1 activity is important in migrating neurons to maintain a high level of Ncad at the plasma membrane for nerve cells to polarise correctly.
Exactly how Ncad interacts with molecular cascades for neuron polarisation is still under investigation. The Neuronal Polarity project accumulated data on which to base a concrete research path for future investigation.
ScienceDaily (July 16, 2012) — Mayo Clinic researchers have found a novel way to monitor real-time chemical changes in the brains of patients undergoing deep brain stimulation (DBS). The groundbreaking insight will help physicians more effectively use DBS to treat brain disorders such as Parkinson’s disease, depression and Tourette syndrome.
The findings are published in the journal Mayo Clinic Proceedings.
Researchers hope to use the discovery to create a DBS system that can instantly respond to chemical changes in the brain. Parkinson’s, Tourette syndrome and depression all involve a surplus or deficiency of neurochemicals in the brain. The idea is to monitor those neurochemicals and adjust them to appropriate levels.
"We can learn what neurochemicals can be released by DBS, neurochemical stimulation, or other stimulation. We can basically learn how the brain works," says author Su-Youne Chang, Ph.D., of the Mayo Clinic Neurosurgery Department. As researchers better understand how the brain works, they can predict changes, and respond before those changes disrupt brain functioning.
Researchers observed the real-time changes of the neurotransmitter adenosine in the brains of tremor patients undergoing deep brain stimulation. Neurotransmitters such as dopamine and serotonin are chemicals that transmit signals from a neuron to a target cell across a synapse.
The team used fast scan cyclic voltammetry (FSCV) to quantify concentrations of adenosine released in patients during deep brain stimulation. The data was recorded using Wireless Instantaneous Neurotransmitter Concentration Sensing, a small wireless neurochemical sensor implanted in the patient’s brain. The sensor, combined with FSCV, scans for the neurotransmitter and translates that information onto a laptop in the operating room. The sensor has previously identified neurotransmitters serotonin and dopamine in tests in brain tissue. This was the first time researchers used this technique in patients.
Tremors are a visual cue that the technique is working; researchers suspect adenosine plays a role in reducing tremors.
Researchers also hope to learn more about conditions without such external manifestations.
"We can’t watch pain as we do tremors," says Kendall Lee, M.D., Ph.D., a Mayo Clinic neurosurgeon. "What is exciting about this electrochemical feedback is that we can monitor the brain without external feedback. So now, we can monitor neurochemicals in the brain and learn about brain processes like pain."
DBS has been used successfully worldwide to treat patients with tremors. However, physicians do not fully understand why DBS works in patients. They know that when DBS electrodes are inserted before electrical stimulation, there is an immediate tremor reduction. Known as the microthalamotomy effect, it is reported in up to 53 percent of patients and known to last as long as a year.
Researchers hope to use the study findings to create a self-contained “smart” DBS system.
"With the stimulator and detection, we can create algorithms and then raise neurotransmitters to a specified level," says Kevin Bennet, a Mayo Clinic engineer who helped create the system. "We can raise these chemicals to appropriate levels, rising and falling with each person throughout their life. Within milliseconds, we can measure, calculate and respond. From the patient’s perspective, this would be essentially instantaneous."
U of S researchers have discovered the chemical pathway that Cannabis sativa uses to create bioactive compounds called cannabinoids, paving the way for the development of marijuana varieties to produce pharmaceuticals or cannabinoid-free industrial hemp.
"What cannabis has done is take a rare fatty acid with a simple, six-carbon chain and use it as a building block to make something chemically complex and pharmacologically active… Now that we know the pathway, we could develop ways to produce cannabinoids with yeast or other microorganisms, which could be a valuable alternative to chemical synthesis for producing cannabinoids for the pharmaceutical industry"
Glial cells, not neurons, are responsible for marijuana-induced forgetfulness
Until recently, most scientists believed that neurons were the all-important brain cells controlling mental functions and that the surrounding glial cells were little more than neuron supporters and “glue.” Now research published in March in Cell reveals that astrocytes, a type of glia, have a principal role in working memory. And the scientists made the discovery by getting mice stoned.
Marijuana impairs working memory—the short-term memory we use to hold on to and process thoughts. Think of the classic stoner who, midsentence, forgets the point he was making. Although such stupor might give recreational users the giggles, people using the drug for medical reasons might prefer to maintain their cognitive capacity.
To study how marijuana impairs working memory, Giovanni Marsicano of the University of Bordeaux in France and his colleagues removed cannabinoid receptors—proteins that respond to marijuana’s psychoactive ingredient THC—from neurons in mice. These mice, it turned out, were just as forgetful as regular mice when given THC: they were equally poor at memorizing the position of a hidden platform in a water pool. When the receptors were removed from astrocytes, however, the mice could find the platform just fine while on THC.
The results suggest that the role of glia in mental activity has been overlooked. Although research in recent years has revealed that glia are implicated in many unconscious processes and diseases [see “The Hidden Brain,” by R. Douglas Fields; Scientific American Mind, May/June 2011], this is one of the first studies to suggest that glia play a key role in conscious thought. “It’s very likely that astrocytes have many more functions than we thought,” Marsicano says. “Certainly their role in cognition is now being revealed.”
Unlike THC’s effect on memory, its pain-relieving property appears to work through neurons. In theory, therefore, it might be possible to design THC-type drugs that target neurons—but not glia—and offer pain relief without the forgetfulness.
The government is to unveil controversial plans to make publicly funded scientific research immediately available for anyone to read for free by 2014, in the most radical shakeup of academic publishing since the invention of the internet. Under the scheme, research papers that describe work paid for by the British taxpayer will be free online for universities, companies and individuals to use for any purpose, wherever they are in the world.
Roke Manor Research Ltd (Roke), a Chemring Group company, has developed the world’s first threat monitoring system for autonomous vehicles that emulates a mammal’s conditioned fear-response mechanism.
The STARTLE system uses a combination of artificial neural network and diagnostic expert systems to continually monitor and assess potential threats.
“Startle delivers local autonomy to a vehicle by providing a mechanism for machine situation awareness to efficiently detect and assess potential threats. This allows vehicle sensing and processing resources to be devoted to the assigned task, but if a threat is detected it will cue the other systems to deal with it swiftly before continuing its mission. These vital seconds could be the difference between mission failure and success.”
FRIDAY, July 13 (HealthDay News) — Movies often stereotype people with schizophrenia as being violent and unpredictable, says a researcher who claims Hollywood dispenses misinformation about symptoms, causes and treatment of this mental illness.
Hollywood portrayals are often inaccurate, misleading, study shows.
For the study, published in the July issue of Psychiatric Services, Patricia Owen of the psychology department at St. Mary’s University in San Antonio, Texas, reviewed 41 English-language films released between 1990 and 2010 that featured at least one main character with schizophrenia.
Owen found that 83 percent of those characters were portrayed as dangerous or violent to others or themselves. Almost one-third engaged in homicidal behavior, and one-quarter committed suicide, the researcher said.
According to the U.S. National Institute of Mental Health, the risk of violence is small among people with schizophrenia. But suicide risk is higher than average. About 10 percent, mostly young men, do kill themselves, the agency notes.
Delusions, auditory and visual hallucinations, and disorganized speech or thought were displayed by most of the characters, the study author pointed out in a news release from the American Psychiatric Association.
But much more common symptoms of schizophrenia — such as flat affect, lack of speech and lack of motivation — were seen much less frequently.
Although schizophrenia incidence is nearly equal among women and men, almost 80 percent of the characters with schizophrenia were male, the study found.
The review noted, however, the movies did get some characterizations of schizophrenia right. Specifically, about half of the characters had low socioeconomic status, which is consistent with data on the illness. Moreover, about half of the movies depicted or alluded to the use of medication to treat the mental illness. Psychotherapy and group therapy were not portrayed often.
Owen suggested that more research is needed to understand how films influence public perceptions about schizophrenia, and to determine how to increase empathy and understanding.
Films featuring a character with schizophrenia include A Beautiful Mind and Donnie Darko.
![ikenbot:
Marijuana Reveals Memory Mechanism
Glial cells, not neurons, are responsible for marijuana-induced forgetfulness
Until recently, most scientists believed that neurons were the all-important brain cells controlling mental functions and that the surrounding glial cells were little more than neuron supporters and “glue.” Now research published in March in Cell reveals that astrocytes, a type of glia, have a principal role in working memory. And the scientists made the discovery by getting mice stoned.
Marijuana impairs working memory—the short-term memory we use to hold on to and process thoughts. Think of the classic stoner who, midsentence, forgets the point he was making. Although such stupor might give recreational users the giggles, people using the drug for medical reasons might prefer to maintain their cognitive capacity.
To study how marijuana impairs working memory, Giovanni Marsicano of the University of Bordeaux in France and his colleagues removed cannabinoid receptors—proteins that respond to marijuana’s psychoactive ingredient THC—from neurons in mice. These mice, it turned out, were just as forgetful as regular mice when given THC: they were equally poor at memorizing the position of a hidden platform in a water pool. When the receptors were removed from astrocytes, however, the mice could find the platform just fine while on THC.
The results suggest that the role of glia in mental activity has been overlooked. Although research in recent years has revealed that glia are implicated in many unconscious processes and diseases [see “The Hidden Brain,” by R. Douglas Fields; Scientific American Mind, May/June 2011], this is one of the first studies to suggest that glia play a key role in conscious thought. “It’s very likely that astrocytes have many more functions than we thought,” Marsicano says. “Certainly their role in cognition is now being revealed.”
Unlike THC’s effect on memory, its pain-relieving property appears to work through neurons. In theory, therefore, it might be possible to design THC-type drugs that target neurons—but not glia—and offer pain relief without the forgetfulness.
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