Most Complete Human Brain Model to Date Is a ‘Brain Changer’

Once licensed, model likely to accelerate study of Alzheimer’s, autism, more

Wednesday, 19 August 2015

Scientists at The Ohio State University have developed a nearly complete human brain in a dish that equals the brain maturity of a 5-week-old foetus.

The brain organoid, engineered from adult human skin cells, is the most complete human brain model yet developed, said Rene Anand, professor of biological chemistry and pharmacology at Ohio State.

The lab-grown brain, about the size of a pencil eraser, has an identifiable structure and contains 99 percent of the genes present in the human foetal brain. Such a system will enable ethical and more rapid and accurate testing of experimental drugs before the clinical trial stage and advance studies of genetic and environmental causes of central nervous system disorders.

“It not only looks like the developing brain, its diverse cell types express nearly all genes like a brain,” Anand said.

“We’ve struggled for a long time trying to solve complex brain disease problems that cause tremendous pain and suffering. The power of this brain model bodes very well for human health because it gives us better and more relevant options to test and develop therapeutics other than rodents.”

Anand reported on his lab-grown brain Tuesday (Aug. 18) at the 2015 Military Health System Research Symposium in Ft. Lauderdale, Florida.

This image of the lab-grown brain is labelled to

show identifiable structures: the cerebral

hemisphere, the optic stalk and the cephalic

flexure, a bend in the mid-brain region, all

characteristic of the human foetal brain. Credit:

courtesy of The Ohio State University.

Anand, who studies the association between nicotinic receptors and central nervous system disorders, was inspired to pursue a model of human neural biology after encountering disappointing results in a rodent study of an experimental autism drug. Taking a chance with a shoestring budget compared to other researchers doing similar projects, he added stem-cell engineering to his research program. Four years later, he had built himself a replica of the human brain.

The main thing missing in this model is a vascular system. What is there – a spinal cord, all major regions of the brain, multiple cell types, signalling circuitry and even a retina – has the potential to dramatically accelerate the pace of neuroscience research, said Anand, also a professor of neuroscience.

“In central nervous system diseases, this will enable studies of either underlying genetic susceptibility or purely environmental influences, or a combination,” he said.

“Genomic science infers there are up to 600 genes that give rise to autism, but we are stuck there. Mathematical correlations and statistical methods are insufficient to in themselves identify causation. You need an experimental system – you need a human brain.”

Converting adult skin cells into pluripotent cells – immature stem cells that can be programmed to become any tissue in the body – is a rapidly developing area of science that earned the researcher who discovered the technique, Shinya Yamanaka, a Nobel Prize in 2012.

“Once a cell is in that pluripotent state, it can become any organ – if you know what to do to support it to become that organ,” Anand said.

“The brain has been the holy grail because of its enormous complexity compared to any other organ. Other groups are attempting to do this as well.”

Anand’s method is proprietary and he has filed an invention disclosure with the university.

He said he used techniques to differentiate pluripotent stem cells into cells that are designed to become neural tissue, components of the central nervous system or other brain regions.

“We provide the best possible environment and conditions that replicate what’s going on in utero to support the brain,” he said of the work he completed with colleague Susan McKay, a research associate in biological chemistry and pharmacology.

High-resolution imaging of the organoid identifies functioning neurons and their signal-carrying extensions – axons and dendrites – as well as astrocytes, oligodendrocytes and microglia. The model also activates markers for cells that have the classic excitatory and inhibitory functions in the brain, and that enable chemical signals to travel throughout the structure.

It takes about 15 weeks to build a model system developed to match the 5-week-old foetal human brain. Anand and McKay have let the model continue to grow to the 12-week point, observing expected maturation changes along the way.

“If we let it go to 16 or 20 weeks, that might complete it, filling in that 1 percent of missing genes. We don’t know yet,” he said.

He and McKay have already used the platform to launch their own projects, creating brain organoid models of Alzheimer’s and Parkinson’s diseases and autism in a dish. They hope that with further development and the addition of a pumping blood supply, the model could be used for stroke therapy studies. For military purposes, the system offers a new platform for the study of Gulf War illness, traumatic brain injury and post-traumatic stress disorder.

Anand hopes his brain model could be incorporated into the Microphysiological Systems program, a platform the Defense Advanced Research Projects Agency is developing by using engineered human tissue to mimic human physiological systems.

Support for the work came from the Marci and Bill Ingram Research Fund for Autism Spectrum Disorders and the Ohio State University Wexner Medical Center Research Fund.

Anand and McKay are co-founders of a Columbus-based start-up company, NeurXstem, to commercialize the brain organoid platform, and have applied for funding from the federal Small Business Technology Transfer program to accelerate its drug discovery applications.

Source: Ohio State University

Contact: Rene Anand

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Scientists Finds Key to Making Neurons from Stem Cells

Pnky, a noncoding RNA found in brain stem cells, may have a broad range of clinical applications

Friday, 20 March 2015

A research team at UC San Francisco has discovered an RNA molecule called Pnky that can be manipulated to increase the production of neurons from neural stem cells.

The research, led by neurosurgeon Daniel A. Lim, MD, PhD, and published on March 19, 2015 in Cell Stem Cell, has possible applications in regenerative medicine, including treatments of such disorders as Alzheimer's disease, Parkinson's disease and traumatic brain injury, and in cancer treatment.

In this cluster of neurons, the greens cells have

been infected with a virus to reduce levels of the

RNA molecule called Pnky, resulting in

increased production of neurons. Someday this

finding could be important for regenerative

medicine and cancer treatment.

Pnky is one of a number of newly discovered long noncoding RNAs (lncRNAs), which are stretches of 200 or more nucleotides in the human genome that do not code for proteins, yet seem to have a biological function.

The name, pronounced "Pinky," was inspired by the popular American cartoon series Pinky and the Brain.

"Pnky is encoded near a gene called 'Brain,' so it sort of suggested itself to the students in my laboratory," said Lim. Pnky also appears only to be found in the brain, he noted.

Co-first authors Alex Ramos, PhD, and Rebecca Andersen, who are students in Lim's laboratory, first studied Pnky in neural stem cells found in mouse brains, and also identified the molecule in neural stem cells of the developing human brain. They found that when Pnky was removed from stem cells in a process called knockdown, neuron production increased three to four times.

"It is remarkable that when you take Pnky away, the stem cells produce many more neurons," said Lim, an assistant professor of neurological surgery and director of restorative surgery at UCSF.

"These findings suggest that Pnky, and perhaps lncRNAs in general, could eventually have important applications in regenerative medicine and cancer treatment."

Lim observed that Pnky has an intriguing possible connection with brain tumours.

Using an analytical technique called mass spectrometry, Ramos found that Pnky binds the protein PTBP1, which is also found in brain tumours and is known to be a driver of brain tumour growth. In neural stem cells, Pnky and PTBP1 appear to function together to suppress the production of neurons.

"Take away one or the other and the stem cells differentiate, making more neurons," said Lim.

"It is also possible that Pnky can regulate brain tumour growth, which means we may have identified a target for the treatment of brain tumours."

Lim said that the larger significance of the research is that it adds to a growing store of knowledge about lncRNAs, previously unknown sections of the genome that some biologists have referred to as the "dark matter" of the human genome.

"Recently, over fifty thousand human lncRNAs have been discovered. Thus, there may be more human lncRNAs than there are genes that code for proteins," said Lim.

"It is possible that not all lncRNAs have important biological functions, but we are making a start toward learning which ones do, and if so, how they function. It's a new world of experimental biology, and the students in my lab are right there on the frontier."

Lim had particular praise for Ramos, an MD-PhD student in the UCSF Medical Scientist Training Program, and Andersen, who has a fellowship from the prestigious National Science Foundation (NSF) Graduate Research Fellowship Program.

"They have been a great collaborative team and an inspiration to others in my lab," said Lim.

"I think they represent the pioneering, investigative spirit of the UCSF student body."

Source: UC San Francisco

Contact: Laura Kurtzman

Reference:

The Long Noncoding RNA Pnky Regulates Neuronal Differentiation of Embryonic and Postnatal Neural Stem Cells

Alexander D. Ramos, Rebecca E. Andersen, Siyuan John Liu, Tomasz Jan Nowakowski, Sung Jun Hong, Caitlyn C. Gertz, Ryan D. Salinas, Hosniya Zarabi, Arnold R. Kriegstein, Daniel A. Lim

Cell Stem Cell, March 19, 2015, DOI: http://dx.doi.org/10.1016/j.stem.2015.02.007

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Do Viruses Make Us Smarter?

Do Viruses Make Us Smarter?

Monday, 12 January 2015

A new study from Lund University in Sweden indicates that inherited viruses that are millions of years old play an important role in building up the complex networks that characterise the human brain.

Researchers have long been aware that endogenous retroviruses constitute around five per cent of our DNA. For many years, they were considered junk DNA of no real use, a side-effect of our evolutionary journey.

In the current study, Johan Jakobsson and his colleagues show that retroviruses seem to play a central role in the basic functions of the brain, more specifically in the regulation of which genes are to be expressed, and when. The findings indicate that, over the course of evolution, the viruses took an increasingly firm hold on the steering wheel in our cellular machinery. The reason the viruses are activated specifically in the brain is probably due to the fact that tumours cannot form in nerve cells, unlike in other tissues.

"We have been able to observe that these viruses are activated specifically in the brain cells and have an important regulatory role. We believe that the role of retroviruses can contribute to explaining why brain cells in particular are so dynamic and multifaceted in their function. It may also be the case that the viruses' more or less complex functions in various species can help us to understand why we are so different", says Johan Jakobsson, head of the research team for molecular neurogenetics at Lund University.

The article, based on studies of neural stem cells, shows that these cells use a particular molecular mechanism to control the activation processes of the retroviruses. The findings provide us with a complex insight into the innermost workings of the most basal functions of the nerve cells. At the same time, the results open up potential for new research paths concerning brain diseases linked to genetic factors.

"I believe that this can lead to new, exciting studies on the diseases of the brain. Currently, when we look for genetic factors linked to various diseases, we usually look for the genes we are familiar with, which make up a mere two per cent of the genome. Now we are opening up the possibility of looking at a much larger part of the genetic material which was previously considered unimportant. The image of the brain becomes more complex, but the area in which to search for errors linked to diseases with a genetic component, such as neurodegenerative diseases, psychiatric illness and brain tumours, also increases".

Source: Lund University

Contact: Johan Jakobsson

Reference:

TRIM28 represses transcription of endogenous retroviruses in neural progenitor cells

Liana Fasching, Adamandia Kapopoulou, Rohit Sachdeva, Rebecca Petri, Marie E. Jönsson, Christian Männe, Priscilla Turelli, Patric Jern, Florence Cammas, Didier Trono, Johan Jakobsson

Cell Reports, 2015 Jan 6;10(1):20-8, doi: 10.1016/j.celrep.2014.12.004

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Human Skin Cells Reprogrammed Directly into Brain Cells

Human Skin Cells Reprogrammed Directly into Brain Cells

Wednesday, 22 October 2014

Scientists have described a way to convert human skin cells directly into a specific type of brain cell affected by Huntington's disease, an ultimately fatal neurodegenerative disorder. Unlike other techniques that turn one cell type into another, this new process does not pass through a stem cell phase, avoiding the production of multiple cell types, the study's authors report.

Scientists have described a way to convert

human skin cells directly into a specific type of

brain cell affected by Huntington's disease, an

ultimately fatal neurodegenerative disorder.

Unlike other techniques that turn one cell type

into another, this new process does not pass

through a stem cell phase, avoiding the

production of multiple cell types, the study's

authors report. The researchers, at Washington

University School of Medicine in St. Louis,

demonstrated that these converted cells survived

at least six months after injection into the brains

of mice and behaved similarly to native cells in

the brain. Human skin cells (top) can be

converted into medium spiny neurons (bottom)

with exposure to the right combination of

microRNAs and transcription factors, according

to work by Andrew Yoo and his research team. 

Credit: Yoo lab.

The researchers, at Washington University School of Medicine in St. Louis, demonstrated that these converted cells survived at least six months after injection into the brains of mice and behaved similarly to native cells in the brain.

"Not only did these transplanted cells survive in the mouse brain, they showed functional properties similar to those of native cells," said senior author Andrew S. Yoo, PhD, assistant professor of developmental biology.

"These cells are known to extend projections into certain brain regions. And we found the human transplanted cells also connected to these distant targets in the mouse brain. That's a landmark point about this paper."

The work appears Oct. 22 in the journal Neuron.

The investigators produced a specific type of brain cell called medium spiny neurons, which are important for controlling movement. They are the primary cells affected in Huntington's disease, an inherited genetic disorder that causes involuntary muscle movements and cognitive decline usually beginning in middle-adulthood. Patients with the condition live about 20 years following the onset of symptoms, which steadily worsen over time.

The research involved adult human skin cells, rather than more commonly studied mouse cells or even human cells at an earlier stage of development. In regard to potential future therapies, the ability to convert adult human cells presents the possibility of using a patient's own skin cells, which are easily accessible and won't be rejected by the immune system.

Scientists have described a way to convert

human skin cells directly into a specific type of

brain cell affected by Huntington's disease, an

ultimately fatal neurodegenerative disorder.

Unlike other techniques that turn one cell type

into another, this new process does not pass

through a stem cell phase, avoiding the

production of multiple cell types, report

researchers at Washington University School of

Medicine in St. Louis. The investigators,

including Andrew Yoo, PhD, (from left) Michelle

Richner and Matheus Victor, demonstrated that

these converted cells survived at least six months

after injection into the brains of mice and

behaved similarly to native cells in the brain. 

Credit: Daniel Abernathy.

To reprogram these cells, Yoo and his colleagues put the skin cells in an environment that closely mimics the environment of brain cells. They knew from past work that exposure to two small molecules of RNA, a close chemical cousin of DNA, could turn skin cells into a mix of different types of neurons.

In a skin cell, the DNA instructions for how to be a brain cell, or any other type of cell, are neatly packed away, unused. In past research published in Nature, Yoo and his colleagues showed that exposure to two microRNAs called miR-9 and miR-124 altered the machinery that governs packaging of DNA. Though the investigators still are unravelling the details of this complex process, these microRNAs appear to be opening up the tightly packaged sections of DNA important for brain cells, allowing expression of genes governing development and function of neurons.

Knowing exposure to these microRNAs alone could change skin cells into a mix of neurons, the researchers then started to fine tune the chemical signals, exposing the cells to additional molecules called transcription factors that they knew were present in the part of the brain where medium spiny neurons are common.

"We think that the microRNAs are really doing the heavy lifting," said co-first author Matheus B. Victor, a graduate student in neuroscience.

"They are priming the skin cells to become neurons. The transcription factors we add then guide the skin cells to become a specific subtype, in this case medium spiny neurons. We think we could produce different types of neurons by switching out different transcription factors."

Yoo also explained that the microRNAs, but not the transcription factors, are important components for the general reprogramming of human skin cells directly to neurons. His team, including co-first author Michelle C. Richner, senior research technician, showed that when the skin cells were exposed to the transcription factors alone, without the microRNAs, the conversion into neurons wasn't successful.

The researchers performed extensive tests to demonstrate that these newly converted brain cells did indeed look and behave like native medium spiny neurons. The converted cells expressed genes specific to native human medium spiny neurons and did not express genes for other types of neurons. When transplanted into the mouse brain, the converted cells showed morphological and functional properties similar to native neurons.

To study the cellular properties associated with the disease, the investigators now are taking skin cells from patients with Huntington's disease and reprogramming them into medium spiny neurons using the approach described in the new paper. They also plan to inject healthy reprogrammed human cells into mice with a model of Huntington's disease to see if this has any effect on the symptoms.

Source: Washington University School of Medicine

Contact: Julia Evangelou Strait

Reference:

Generation of human striatal neurons by microRNA-dependent direct conversion of fibroblasts

Victor MB, Richner M, Hermanstyne TO, Ransdell JL, Sobieski C, Deng PY, Klyachko VA, Nerbonne JM, Yoo AS

Neuron. Oct. 22, 2014, Volume 84, Issue 2, p311–323

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Stem Cells Use 'First Aid Kits' to Repair Damage

Stem Cells Use 'First Aid Kits' to Repair Damage

Thursday, 18 September 2014

Stem cells hold great promise as a means of repairing cells in conditions such as multiple sclerosis, stroke or injuries of the spinal cord because they have the ability to develop into almost any cell type. Now, new research shows that stem cell therapy can also work through a mechanism other than cell replacement.

Confocal super resolution imaging of the rapid

(2h) up-take of CD63-RFP EVs packed via

target cell fEGFP (green) plasma membrane in

vitro. Credit: Design and artwork by CongJian

Zhao.

In a study published today in Molecular Cell, a team of researchers led by the University of Cambridge has shown that stem cells "communicate" with cells by transferring molecules via fluid filled bags called vesicles, helping other cells to modify the damaging immune response around them.

Although scientists have speculated that stem cells might act rather like drugs – in sensing signals, moving to specific areas of the body and executing complex reactions – this is the first time that a molecular mechanism for this process has been demonstrated. By understanding this process better, researchers can identify ways of maximising the efficiency of stem-cell-based therapies.

Dr Stefano Pluchino from the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, who led the study, said:

"These tiny vesicles in stem cells contain molecules like proteins and nucleic acids that stimulate the target cells and help them to survive – they act like mini "first aid kits".

"Essentially, they mirror how the stem cells respond to an inflammatory environment like that seen during complex neural injuries and diseases, and they pass this ability on to the target cells. We think this helps injured brain cells to repair themselves."

Mice with damage to brain cells – such as the damage seen in multiple sclerosis – show a remarkable level of recovery when neural stem/precursor cells (NPCs) are injected into their circulatory system. It has been suggested that this happens because the NPCs discharge molecules that regulate the immune system and that ultimately reduce tissue damage or enhance tissue repair.

The team of researchers from the UK, Australia, Italy, China and Spain has now shown that NPCs make vesicles when they are in the vicinity of an immune response, and especially in response to a small protein, or cytokine, called Interferon-gamma which is released by immune cells. This protein has the ability to regulate both the immune responses and intrinsic brain repair programmes and can alter the function of cells by regulating the activity of scores of genes.

Their results show that a highly specific pathway of gene activation is triggered in NPCs by IFN-gamma, and that this protein also binds to a receptor on the surface of vesicles. When the vesicles are released by the NPCs, they adhere and are taken up by target cells. Not only does the target cell receive proteins and nucleic acids that can help them self-repair, but it also receives the IFN-gamma on the surface of the vesicles, which activates genes within the target cells.

The researchers, who were funded by the European Research Council and the Italian MS Society, used electron microscopy and super resolution imaging to visualise the vesicles moving between the NPCs and target cells in vitro.

"Our work highlights a surprising novel role for stem-cell-derived vesicles in propagating responses to the environment," added Pluchino.

"It represents a significant advance in understanding the many levels of interaction between stem cells and the immune system, and a new molecular mechanism to explain how stem-cell therapy works."

Source: University of Cambridge

Contact: Louise Walsh

Reference:

Extracellular Vesicles from Neural Stem Cells Transfer IFN-γ via Ifngr1 to Activate Stat1 Signaling in Target Cells

Chiara Cossetti, Nunzio Iraci, Tim R. Mercer, Tommaso Leonardi, Emanuele Alpi, Denise Drago, Clara Alfaro-Cervello, Harpreet K. Saini, Matthew P. Davis, Julia Schaeffer, Beatriz Vega, Matilde Stefanini, CongJian Zhao, Werner Muller, Jose Manuel Garcia-Verdugo, Suresh Mathivanan, Angela Bachi, Anton J. Enright, John S. Mattick, Stefano Pluchino

Molecular Cell, September 18, 2014, DOI: http://dx.doi.org/10.1016/j.molcel.2014.08.020

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Suspect Gene Corrupts Neural Connections

'Diseases of synapses' demonstrated in a dish

Monday, 18 August 2014

Researchers have long suspected that major mental disorders are genetically-rooted diseases of synapses – the connections between neurons. Now, investigators supported in part by the National Institutes of Health have demonstrated in patients' cells how a rare mutation in a suspect gene disrupts the turning on and off of dozens of other genes underlying these connections.

Synapses – sites of intercellular communications

– are revealed in a mature iPSC cortex neuron

derived from a participant in the study. Immune-

based staining shows synapse markers (red,

green) and the cell's nucleus (blue). Credit:

Hongjun Song, Ph.D., Johns Hopkins University.

"Our results illustrate how genetic risk, abnormal brain development and synapse dysfunction can corrupt brain circuitry at the cellular level in complex psychiatric disorders," explained Hongjun Song, Ph.D., of Johns Hopkins University, Baltimore, a grantee of the NIH's National Institute of Mental Health (NIMH), a founder of the study.

Song and colleagues, from universities in the United States, China, and Japan, report on their discovery in the journal Nature, August 17, 2014.

"The approach used in this study serves as a model for linking genetic clues to brain development," said NIMH director Thomas R. Insel, M.D..

Most major mental disorders, such as schizophrenia, are thought to be caused by a complex interplay of multiple genes and environmental factors. However, studying rare cases of a single disease-linked gene that runs in a family can provide shortcuts to discovery. Decades ago, researchers traced a high prevalence of schizophrenia and other major mental disorders – which often overlap genetically – in a Scottish clan to mutations in the gene DISC1 (Disrupted In Schizophrenia-1). But until now, most of what's known about cellular effects of such DISC1 mutations has come from studies in the rodent brain.

To learn how human neurons are affected, Song's team used a disease-in-a-dish technology called induced pluripotent stem cells (iPSCs). A patient's skin cells are first induced to revert to stem cells. Stem cells play a critical role in development of the organism by transforming into the entire range of specialized cells which make up an adult. In this experiment, these particular "reverted" stem cells were coaxed to differentiate into neurons, which could be studied developing and interacting in a petri dish. This makes it possible to pinpoint, for example, how a particular patient's mutation might impair synapses. Song and colleagues studied iPSCs from four members of an American family affected by DISC1-linked schizophrenia and genetically related mental disorders.

Strikingly, iPSC-induced neurons, of a type found in front brain areas implicated in psychosis, expressed 80 percent less of the protein made by the DISC1 gene in family members with the mutation, compared to members without the mutation. These mutant neurons showed deficient cellular machinery for communicating with other neurons at synapses.

The researchers traced these deficits to errant expression of genes known to be involved in synaptic transmission, brain development, and key extensions of neurons where synapses are located. Among these abnormally expressed genes were 89 previously linked to schizophrenia, bipolar disorder, depression, and other major mental disorders. This was surprising, as DISC1's role as a hub that regulates expression of many genes implicated in mental disorders had not previously been appreciated, say the researchers.

The clincher came when researchers experimentally produced the synapse deficits by genetically engineering the DISC1 mutation into otherwise normal iPSC neurons – and, conversely, corrected the synapse deficits in DISC1 mutant iPSC neurons by genetically engineering a fully functional DISC1 gene into them. This established that the DISC1 mutation, was, indeed the cause of the deficits.

The results suggest a common disease mechanism in major mental illnesses that integrates genetic risk, aberrant neurodevelopment, and synapse dysfunction. The overall approach may hold promise for testing potential treatments to correct synaptic deficits, say the researchers.

Source: NIH/National Institute of Mental Health 

Contact: Jules Asher

Reference:

Synaptic dysregulation in a human iPS cell model of major mental disorders 

Wen Z, Nguyen HN, Guo Z, Lalli MA, Wang X, Su Y, Kim N-S, Yoon K-J, Shin J, Zhang C, Makri G, Nauen D, Yu H, Guzman E, Chiang C-H, Yoritomo N, Kaibuchi K, Zou J, Christian KM, Cheng L, Ross CA, Margolis RL, Chen G, Kosik KS, Song H, Ming G

Nature, Aug. 17, 2014, doi:10.1038/nature13716

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Stem Cells Reveal How Schizophrenia-linked Genetic Variation Affects Neurons

Stem Cells Reveal How Schizophrenia-linked Genetic Variation Affects Neurons

Monday, 18 August 2014

A genetic variation linked to schizophrenia, bipolar disorder and severe depression wreaks havoc on connections among neurons in the developing brain, a team of researchers reports. The study, led by Guo-li Ming, M.D., Ph.D., and Hongjun Song, Ph.D., of the Johns Hopkins University School of Medicine and described online Aug. 17 in the journal Nature, used stem cells generated from people with and without mental illness to observe the effects of a rare and pernicious genetic variation on young brain cells. The results add to evidence that several major mental illnesses have common roots in faulty "wiring" during early brain development.

In this image, cell nuclei are shown in blue and

synapses in red and green. Credit: Zhexing Wen-

Johns Hopkins Medicine.

"This was the next best thing to going back in time to see what happened while a person was in the womb to later cause mental illness," says Ming.

"We found the most convincing evidence yet that the answer lies in the synapses that connect brain cells to one another."

Previous evidence for the relationship came from autopsies and from studies suggesting that some genetic variants that affect synapses also increase the chance of mental illness. But those studies could not show a direct cause-and-effect relationship, Ming says.

One difficulty in studying the genetics of common mental illnesses is that they are generally caused by environmental factors in combination with multiple gene variants, any one of which usually could not by itself cause disease. A rare exception is the gene known as disrupted in schizophrenia 1 (DISC1), in which some mutations have a strong effect. Two families have been found in which many members with the DISC1 mutations have mental illness.

Video of human neurons firing. Credit: Zhexing

Wen-Johns Hopkins Medicine.

To find out how a DISC1 variation with a few deleted DNA "letters" affects the developing brain, the research team collected skin cells from a mother and daughter in one of these families who have neither the variation nor mental illness, as well as the father, who has the variation and severe depression, and another daughter, who carries the variation and has schizophrenia. For comparison, they also collected samples from an unrelated healthy person. Postdoctoral fellow Zhexing Wen, Ph.D., coaxed the skin cells to form five lines of stem cells and to mature into very pure populations of synapse-forming neurons.

After growing the neurons in a dish for six weeks, collaborators at Pennsylvania State University measured their electrical activity and found that neurons with the DISC1 variation had about half the number of synapses as those without the variation. To make sure that the differences were really due to the DISC1 variation and not to other genetic differences, graduate student Ha Nam Nguyen spent two years making targeted genetic changes to three of the stem cell lines.

In one of the cell lines with the variation, he swapped out the DISC1 gene for a healthy version. He also inserted the disease-causing variation into one healthy cell line from a family member, as well as the cell line from the unrelated control. Sure enough, the researchers report, the cells without the variation now grew the normal amount of synapses, while those with the inserted mutation had half as many.

"We had our definitive answer to whether this DISC1 variation is responsible for the reduced synapse growth," Ming says.

To find out how DISC1 acts on synapses, the researchers also compared the activity levels of genes in the healthy neurons to those with the variation. To their surprise, the activities of more than 100 genes were different.

"This is the first indication that DISC1 regulates the activity of a large number of genes, many of which are related to synapses," Ming says.

The research team is now looking more closely at other genes that are linked to mental disorders. By better understanding the roots of mental illness, they hope to eventually develop better treatments for it, Ming says.

Source: Johns Hopkins Medicine 

Contact: Shawna Williams

Reference:

Synaptic dysregulation in a human iPS cell model of major mental disorders 

Wen Z, Nguyen HN, Guo Z, Lalli MA, Wang X, Su Y, Kim N-S, Yoon K-J, Shin J, Zhang C, Makri G, Nauen D, Yu H, Guzman E, Chiang C-H, Yoritomo N, Kaibuchi K, Zou J, Christian KM, Cheng L, Ross CA, Margolis RL, Chen G, Kosik KS, Song H, Ming G

Nature, Aug. 17, 2014, doi:10.1038/nature13716

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For more on stem cells and cloning, go to CellNEWS at

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Umbilical Cord Blood, at the Cutting Edge of Today’s Medicine

“Saving Grace”

From: Al Jazeera America’s TECHKNOW Presents

Thursday, 17 July 2014

This Saturday, July 19th at 7:30 pm ET/4:30 pm PT, Al Jazeera America’s “TechKnow” shows us one of the most exiting areas of medical research – how umbilical cord blood is being used to treat brain disease and injury.

Dr. Joanne Kurtzberg. Credit: Al Jazeera.

“Techknow” host and mechanical engineer Dr. Shini Somara takes us inside Duke Children’s Hospital, where a team of doctors is treating young Grace Matthews, an infant with hydrocephalus, or water on the brain, characterized by the tell-tale swelling of the baby’s head.  We go behind-the-scenes on the high-tech experimental treatments, as doctors infuse Grace with stem cells from her own umbilical cord, and we meet another young patient who experienced “miraculous” progress from the use of umbilical cord stem cells.

The medical equivalent of gold, we’re just at the tip of understanding how stem cells from cord blood, harvested at the time of birth, can be used to help the brain regenerate and heal from injuries and damage.

“I personally believe cell therapy, and regenerative medicine, is going to be the next big advance in medicine, and that cells like cord blood are going to drive that forward,” reports Dr. Joanne Kurtzberg, Chief of the Division of Pediatric Blood and Marrow Transplantation at Duke University Medical Center in Durham, North Carolina.

The program is airing Saturday, July 19th at 7:30PET/4:30P PT;

Repeats 10:30P ET/7:30P PT

Find Al Jazeera America near you: www.aljazeera.com/getajam

About Al Jazeera America’s “TechKnow”:

Al Jazeera America’s “TechKnow” is a half hour documentary show that airs weekly on Saturdays at 7:30 pm ET/4:30 pm PT.  A show about innovations that can change lives, “TechKnow” explores the intersection of hardware and humanity in a unique way – it’s a show about science, by scientists. “TechKnow” rotating cast of hosts includes mechanical engineer Dr. Shini Somara, molecular neuroscientist Dr. Crystal Dilworth, entolomologist Phil Torres, biologist Marita Davison, engineer Kosta Grammatis, science writer Kyle Hill, former CIA operative and analyst Lindsay Moran, neuroscientist Rachelle Oldmixon and neurobiologist Cara Santa Maria.

Source: Al Jazeera America’s “TechKnow”

Contact: Jocelyn Austin, Director, Publicity

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ZenMaster

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For more on stem cells and cloning, go to CellNEWS at

http://cellnews-blog.blogspot.com/

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'Master Switch' for Myelination in Human Brain Stem Cells is Identified

Finding is key to developing MS treatments using stem cells

Tuesday, 01 July 2014

The identification of the transcription factor,

SOX10, in human brain cells, brings researchers

closer to the goal of treating multiple sclerosis

(MS) by transplanting into patients the brain cells

that make myelin. Credit: Jing Wang. 

Scientists at the University at Buffalo have identified the single transcription factor or "master switch" that initiates the critical myelination process in the brain. The research will be published online in Proceedings of the National Academy of Sciences (PNAS) on June 30.

The identification of this factor, SOX10, in human brain cells, brings researchers closer to the goal of treating multiple sclerosis (MS) by transplanting into patients the brain cells that make myelin.

"Now that we have identified SOX10 as an initiator of myelination, we can work on developing a viral or pharmaceutical approach to inducing it in MS patients," says Fraser Sim, PhD, senior author on the paper and assistant professor in the UB Department of Pharmacology and Toxicology in the School of Medicine and Biomedical Sciences.

"If we could create a small molecule drug that would switch on SOX10, that would be therapeutically important," he adds.

Stem cell therapy is seen as having dramatic potential for treating MS, but there are key obstacles, especially the length of time it takes for progenitor cells to turn into oligodendrocytes, the brain's myelin-making cells.

Using currently available methods, Sim explains, it can take as long as a year to generate a sufficient number of human oligodendrocyte cells to treat a single MS patient.

That's partly because there are so many steps: the skin or blood cell must be turned into induced pluripotent stem cells, which can differentiate into any other type of cell and from which neural progenitor cells can be produced. Those progenitor cells then must undergo differentiation to oligodendrocyte progenitors that are capable of ultimately producing the oligodendrocytes.

"Ideally, we'd like to get directly to oligodendrocyte progenitors," says Sim.

"The new results are a stepping stone to the overall goal of being able to take a patient's skin cells or blood cells and create from them oligodendrocyte progenitors," he says.

Using foetal (not embryonic) brain stem cells, the UB researchers searched for transcription factors that are absent in neural progenitor cells and switched on in oligodendrocyte progenitor cells.

While neural progenitor cells are capable of producing myelin, they do so very poorly and can cause undesirable outcomes in patients, so the only candidate for transplantation is the oligodendrocyte progenitor.

"The ideal cell to transplant is the oligodendrocyte progenitor cell," Sim says.

"The question was, could we use one of these transcription factors to turn the neural progenitor cell into an oligodendrocyte progenitor cell?"

To find out, they looked at different characteristics, such as mRNA expression, protein and whole gene expression and functional studies.

"We narrowed it down to a short list of 10 transcription factors that were made exclusively by oligodendrocyte progenitor cells," says Sim.

"Among all 10 factors that we studied, only SOX10 was able to make the switch from neural progenitor to oligodendrocyte progenitor cell," says Sim.

In addition, the UB researchers found that SOX10 could expedite the transformation from oligodendrocyte progenitor cell to differentiation as an oligodendrocyte, the myelin-producing cell and the ultimate treatment goal for MS.

"SOX10 facilitates both steps," says Sim.

That's tantalizing, he says, because one of the biggest problems with MS is that cells get stuck in the step between the oligodendrocyte progenitor cell and the oligodendrocyte.

"In MS, first the immune system attacks the brain, but the brain is unable to repair itself effectively," explains Sim.

"If we could boost the regeneration step by facilitating formation of oligodendrocytes from progenitor cells, then we might be able to keep patients in the relapsing remitting stage of MS, a far less burdensome stage of disease than the later, progressive stage."

Sim is also an investigator with other scientists at UB and the University of Rochester on the $12.1 million New York State Stem Cell Science award led by SUNY Upstate Medical Center. The research will test the safety and effectiveness of implanting stem cells that can reproduce myelin into the central nervous system of MS patients.

Source: University at Buffalo 

Contact: Ellen Goldbaum

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ZenMaster

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For more on stem cells and cloning, go to CellNEWS at

http://cellnews-blog.blogspot.com/

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