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  • richardmitnick 6:20 pm on June 26, 2017 Permalink | Reply
    Tags: , , , CrY2H-seq, Interactome, New method to rapidly map the “social networks” of proteins, , Salk Institute   

    From Salk: “New method to rapidly map the ‘social networks’ of proteins” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    June 26, 2017

    Salk scientists improved upon a classic approach to mapping the interactions between proteins.

    1
    A new mapping method let researchers discover new links (gray lines) between two groups of plant proteins (yellow and blue) that have a common structure (the BBX domain), suggesting many different combinations of interactions, rather than a few, are involved in coordinating cellular programs like flowering time and circadian rhythm. Credit: Salk Institute

    Salk scientists have developed a new high-throughput technique to determine which proteins in a cell interact with each other. Mapping this network of interactions, or “interactome,” has been slow going in the past because the number of interactions that could be tested at once was limited. The new approach, published June 26 in Nature Methods, lets researchers test millions of relationships between thousands of proteins in a single experiment.

    “The power of this new approach is in the ability we now have to scale it up,” says senior author Joseph Ecker, professor and director of Salk’s Genomic Analysis Laboratory and investigator of the Howard Hughes Medical Institute. “This assay has the potential to begin to address questions about fundamental biological interactions that we haven’t been able to address before.”

    The interactome of a cell, like a map of social networks, lets scientists see who’s working with who in the world of proteins. This helps them figure out the roles of different proteins and piece together the different players in molecular pathways and processes. If a newly discovered protein interacts with lots of other proteins involved in cellular metabolism, for instance, researchers can deduce that’s a likely role for the new protein and potentially target it for treatments related to metabolic dysfunction.

    Until now, researchers have typically relied on standard high-throughput yeast two-hybrid (Y2H) assays to determine the interactions between proteins. The system requires using a single known protein—known as the “bait”—to screen against a pool of “prey” proteins. But finding all the interactions between, for instance, 1,000 proteins, would require 1000 separate experiments to screen once for each bait’s interaction partners.

    “Current technologies essentially require that interactions detected in primary screening get retested individually,” says Shelly Trigg, an NSF Graduate Research Fellow at the University of California, San Diego, in the Ecker lab, and first author of the new paper. “That may no longer be necessary with the screening depth this approach achieves.”

    In their new method, Ecker, Trigg and their colleagues added a twist to the standard Y2H assay for a much more effective way of measuring the interactome. The genes for two proteins, each on their own circle of DNA, are added to the same cell. If the proteins of interest interact inside the cell, a gene called Cre is activated. When turned on, Cre physically splices the two individual circles of DNA together, thus pairing the genes of interacting proteins together so the team can easily find them through sequencing. The team can generate a massive library of yeast cells—each containing different pairs of proteins by introducing random combinations of genes on circular DNA called plasmids. When cells are positive for a protein interaction, the researchers can use genetic sequencing to figure out what the two proteins interacting are, using new high-throughput DNA sequencing technologies similar to those used for human genome sequencing. This way, they’re no longer limited to testing one “bait” protein at a time, but could test the interactions between all the proteins in a library at once.

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    Joseph Ecker (courtesy of Salk Institute) and Shelly Trigg (courtesy of Austin Trigg)

    Ecker’s group tested the new method, dubbed CrY2H-seq, on all the transcription factors—a large class of proteins—in the plant Arabidopsis.

    “When you take 1,800 proteins and test the interactions among them, that’s nearly 4 million combinations,” says Ecker. “We did that ten times in a matter of a month.”

    They revealed more than 8,000 interactions among those proteins tested, giving them new insight into which Arabidopsis transcription factors interact with each other. The data, they say, helps answer longstanding questions about whether certain groups of transcription factors have set functions. Some of the poorly understood transcription factors, they found, interact with more well-understood factors that regulate the plant’s response to auxin, a hormone involved in coordinating plant growth.

    In the future, the method could be scaled up to test larger sets of proteins—human cells, for instance, contain about 20,000 different proteins. This easier and faster method to determine the entire interactome of a cell also opens up the possibility of studying how the interactome changes under different conditions—an experiment that’s never been possible in the past.

    Other researchers on the study were Renee Garza, Andrew MacWilliams, Joseph Nery, Anna Bartlett, Rosa Castanon, Adeline Goubil, Joseph Feeney, Ronan O’Malley, Shao-shan Carol Huang, Zhuzhu Zhang, and Mary Galli of the Salk Institute.

    The work and the researchers involved were supported by grants from the U.S. Department of Energy, National Science Foundation Graduate Research Fellowship Program, Howard Hughes Medical Institute, and Mary K. Chapman Foundation.

    See the full article here .

    Please help promote STEM in your local schools.

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    Salk Institute Campus

    Every cure has a starting point. Like Dr. Jonas Salk when he conquered polio, Salk scientists are dedicated to innovative biological research. Exploring the molecular basis of diseases makes curing them more likely. In an outstanding and unique environment we gather the foremost scientific minds in the world and give them the freedom to work collaboratively and think creatively. For over 50 years this wide-ranging scientific inquiry has yielded life-changing discoveries impacting human health. We are home to Nobel Laureates and members of the National Academy of Sciences who train and mentor the next generation of international scientists. We lead biological research. We prize discovery. Salk is where cures begin.

     
  • richardmitnick 5:01 am on June 14, 2017 Permalink | Reply
    Tags: , , Salk Institute, The Waitt Center, ZEISS   

    From Salk: “Salk’s Waitt Advanced Biophotonics Center partners with imaging giant ZEISS’ 

    Salk Institute bloc

    Salk Institute for Biological Studies

    June 7, 2017
    Office of Communications
    Tel: (858) 453-4100
    press@salk.edu

    Global partnership will advance biomedical imaging technologies.

    The Salk Institute’s Waitt Advanced Biophotonics Center and ZEISS announced today a global partnership to accelerate the frontiers of microscopy and imaging technologies.

    The Waitt Center, launched in 2011 with a landmark $20 million gift from Salk Board Chair Ted Waitt’s Waitt Foundation and supported by federal grants, serves as a state-of-the-art research hub, offering next-generation imaging, visualization and data analysis tools to researchers from across many biological disciplines including cancer, neuroscience, plant biology and immunology.

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    From left to right: James A. Sharp, President, Carl Zeiss Microscopy LLC; Uri Manor, PhD, Waitt Advanced Biophotonics Center Core Director; Elizabeth Blackburn, PhD, President, Salk Institute; Jacob A. James, Managing Director, Waitt Foundation. Credit: Salk Institute

    Now, the Waitt Center’s partnership with ZEISS, a global, Germany-based company that develops cutting-edge optical and optoelectronic technologies, will enable access to ZEISS’ state-of-the-art technology before it’s commercially available. ZEISS will collaborate with Salk scientists to receive critical feedback on challenging imaging needs to further push the boundaries of imaging technologies to new frontiers.

    “Overall, this is a unique opportunity that gives Salk scientists a chance to not only benefit from ZEISS technology as it is being developed, but also to influence how the next generation of microscopes are designed,” says Uri Manor, director of the Waitt Advanced Biophotonics Center core and Salk staff scientist.

    Imaging and the accompanying data needed to capture higher resolution visuals are becoming more essential to biomedical research. “We are delighted to have this opportunity to help advance critical technology so essential to many areas of cutting-edge biological fields,” adds Elizabeth Blackburn, president of the Salk Institute. “This partnership enables us to have access to the latest imaging technology, and will have tremendous impact on our ability to visualize and better understand the workings of biology and disease.”

    ZEISS recently assisted the Waitt Center with an expansion microscopy workshop, which is expected to be the first of many hands-on workshops and courses supported by ZEISS personnel and equipment. In the future, the partnership will reach full force as the Waitt Center collaborates with ZEISS to develop, test, optimize and perform next-generation biological imaging experiments with alpha and beta versions of hardware and software for everything from high-speed 4D fluorescence imaging to cryo-correlative fluorescence and electron microscopy.

    “The ZEISS labs@location Partnership Program is a community of key customers and partners providing in-depth knowledge and dedicated services to support our microscopy business,” says Jim Sharp, president of Carl Zeiss Microscopy, LLC. “We are very excited to work more closely with the Salk Institute to not only improve our West Coast presence, but also better understand and respond to the ever-changing needs of our user base.”

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Salk Institute Campus

    Every cure has a starting point. Like Dr. Jonas Salk when he conquered polio, Salk scientists are dedicated to innovative biological research. Exploring the molecular basis of diseases makes curing them more likely. In an outstanding and unique environment we gather the foremost scientific minds in the world and give them the freedom to work collaboratively and think creatively. For over 50 years this wide-ranging scientific inquiry has yielded life-changing discoveries impacting human health. We are home to Nobel Laureates and members of the National Academy of Sciences who train and mentor the next generation of international scientists. We lead biological research. We prize discovery. Salk is where cures begin.

     
  • richardmitnick 7:52 am on June 8, 2017 Permalink | Reply
    Tags: , , How cells divide tasks and conquer work, Salk Institute   

    From Salk: “How cells divide tasks and conquer work” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    June 7, 2017
    No writer credit found

    Salk scientist provides theoretical framework for understanding biological complexity.

    Despite advances in neuroscience, the brain is still very much a black box—no one even knows how many different types of neurons exist. Now, a scientist from the Salk Institute has used a mathematical framework to better understand how different cell types divide work among themselves.

    The theory, which is described in the journal Neuron on June 7, 2017, could help reveal how cell types achieve greater efficiency and reliability or how disease results when the division of labor is not as effective.

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    Tatyana Sharpee. Salk.

    “Understanding how different cell types work together is a big unknown in biology,” says Tatyana Sharpee, an associate professor in Salk’s Computational Neurobiology Laboratory and holder of the Helen McLoraine Developmental Chair. “For example, in the brain we do not know yet the number of different cell types, with ongoing debates on what even constitutes a cell type. Having a theoretical framework such as this one can focus experimental efforts for understanding biological complexity.”

    In the 1950s, information theory was developed to study how to send messages in the most cost-effective manner while minimizing errors. This theory is also relevant for how neurons in the brain communicate with each other. Sharpee, who uses information theory to discern fundamental laws governing biological complexity, says it can help predict how many different cell types to expect in a system and how these cell types should work together.

    Sharpee and colleagues published this idea in 2015 in Proceedings of the National Academy of Sciences, explaining why neurons in the salamander retina that are sensitive to dimming lights split into two sub-types, whereas comparable neurons sensitive to increases in light do not. It turns out that neurons sensitive to light dimming are more reliable than neurons sensitive to light increases. The increased reliability of dark-sensitive neurons means they can represent signals of different strengths separately whereas neurons sensitive to light increases have to work together, in effect averaging their responses.

    This theory has an analogy in real life, Sharpee explains: “When trainees are new, managers often assign the same task to several people. If they get the same or very similar answers, a manager can have more confidence in the work. Once trainees are proficient, managers can trust them enough to give each more specialized tasks.”

    In this analogy, less reliable neurons are like trainees, whose answers need to be averaged because they might all be slightly off. More reliable neurons are the proficient workers, who can be given different tasks because each one’s accuracy can be trusted.

    In the new paper, Sharpee further describes how these arguments can be generalized to help us understand how different proteins (such as ion channels that help us produce signals in the brain in the first place) divide the input ranges to achieve greater overall efficiency for the organism. Based on information theory, the arguments can also be applied outside of neuroscience.

    “The theory that we tested in the retina can be relevant for understanding the complexity of many other systems, because if you have noisy input-output elements it’s better to average their output. And if the elements are slightly more capable they can be more specific and divide up the dynamic range,” adds Sharpee. She is working with a number of groups to test and broaden the range of applications, such as inflammation, mood disorders, metabolism and cancer.

    The work was funded by the National Science Foundation.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Salk Institute Campus

    Every cure has a starting point. Like Dr. Jonas Salk when he conquered polio, Salk scientists are dedicated to innovative biological research. Exploring the molecular basis of diseases makes curing them more likely. In an outstanding and unique environment we gather the foremost scientific minds in the world and give them the freedom to work collaboratively and think creatively. For over 50 years this wide-ranging scientific inquiry has yielded life-changing discoveries impacting human health. We are home to Nobel Laureates and members of the National Academy of Sciences who train and mentor the next generation of international scientists. We lead biological research. We prize discovery. Salk is where cures begin.

     
  • richardmitnick 7:35 am on June 2, 2017 Permalink | Reply
    Tags: Alzheimer’s Parkinson’s and Huntington’s diseases as well as schizophrenia autism and depression., , , , , Microglia–unique, Salk Institute   

    From Salk: “Brain’s immune cells linked to Alzheimer’s, Parkinson’s, schizophrenia” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    Salk and UC San Diego scientists conducted vast microglia survey, revealing links to neurodegenerative diseases and psychiatric illnesses.

    Scientists have, for the first time, characterized the molecular markers that make the brain’s front lines of immune defense–cells called microglia–unique. In the process, they discovered further evidence that microglia may play roles in a variety of neurodegenerative and psychiatric illnesses, including Alzheimer’s, Parkinson’s and Huntington’s diseases as well as schizophrenia, autism and depression.

    “Microglia are the immune cells of the brain, but how they function in the human brain is not well understood,” says Rusty Gage, professor in Salk’s Laboratory of Genetics, the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease, and a senior author of the new work. “Our work not only provides links to diseases but offers a jumping off point to better understand the basic biology of these cells.”

    Genes that have previously been linked to neurological diseases are turned on at higher levels in microglia compared to other brain cells, the team reported in Science on May 25, 2017. While the link between microglia and a number of disorders has been explored in the past, the new study offers a molecular basis for this connection.

    “These studies represent the first systematic effort to molecularly decode microglia,” says Christopher Glass, a Professor of Cellular and Molecular Medicine and Professor of Medicine at University of California San Diego, also senior author of the paper. “Our findings provide the foundations for understanding the underlying mechanisms that determine beneficial or pathological functions of these cells.”

    Microglia are a type of macrophage, white blood cells found throughout the body that can destroy pathogens or other foreign materials. They’re known to be highly responsive to their surroundings and respond to changes in the brain by releasing pro-inflammatory or anti-inflammatory signals. They also prune back the connections between neurons when cells are damaged or diseased. But microglia are notoriously hard to study. They can’t be easily grown in a culture dish and quickly die outside of a living brain.

    Nicole Coufal, a pediatric critical care doctor at UC San Diego, who also works in the Gage lab at Salk, wanted to make microglia from stem cells. But she realized there wasn’t any way to identify whether the resulting cells were truly microglia.

    “There was not a unique marker that differentiated microglia from circulating macrophages in the rest of the body,” she says.

    David Gosselin and Dylan Skola in the Glass lab, together with Coufal and their collaborators, set out to characterize the molecular characteristics of microglia. They worked with neurosurgeons at UC San Diego to collect brain tissue from 19 patients, all of who were having brain surgery for epilepsy, a brain tumor or a stroke. They isolated microglia from areas of tissue that were unaffected by disease, as well as from mouse brains, and then set out to study the cells. The work was made possible by a multidisciplinary collaboration between bench scientists, bioinformaticians and clinicians.

    The team used a variety of molecular and biochemical tests–performed within hours of the cells being collected–to characterize which genes are turned on and off in microglia, how the DNA is marked up by regulatory molecules, and how these patterns change when the cells are cultured.

    Microglia, they found, have hundreds of genes that are more highly expressed than other types of macrophages, as well as distinct patterns of gene expression compared to other types of brain cells. After the cells were cultured, however, the gene patterns of the microglia began to change. Within just six hours, more than 2,000 genes had their expression turned down by at least fourfold. The results underscore how dependent microglia are on their surroundings in the brain, and why researchers have struggled to culture them.

    Next, the researchers analyzed whether any of the genes that were upregulated in microglia compared to other cells had been previously implicated in disease. Genes linked to a variety of neurodegenerative and psychiatric diseases, they found, were highly expressed in microglia.

    “A really high proportion of genes linked to multiple sclerosis, Parkinson’s and schizophrenia are much more highly expressed in microglia than the rest of the brain,” says Coufal. “That suggests there’s some kind of link between microglia and the diseases.”

    For Alzheimer’s, more than half of the genes known to affect a person’s risk of developing the disease were expressed more highly in microglia than other brain cells.

    In mice, however, many of the disease genes weren’t as highly expressed in microglia. “That tells us that maybe mice aren’t the best model organisms for some of these diseases,” Coufal says.

    More work is needed to understand exactly how microglia may be altered in people with diseases, but the new molecular profile of microglia offers a way for researchers to begin trying to better culture the cells, or coax stem cells to develop into microglia for future studies.

    Other researchers on the study were Baptiste Jaeger, Carolyn O’Connor, Conor Fitzpatrick, Monique Pena, and Amy Adair of the Salk Institute; Inge Holtman, Johannes Schlachetzki, Eniko Sajti, Martina Pasillas, David Gona, and Michael Levy of the University of California San Diego; and Richard Ransohoff of Biogen.

    The work and the researchers involved were supported by grants from the Larry L. Hillblom Foundation, National Institutes of Health, Canadian Institute of Health Research, Multiple Sclerosis Society of Canada, University of California San Diego, Dutch MS Research Foundation, the Gemmy and Mibeth Tichelaar Foundation, the DFG, the JPB Foundation, Dolby Family Ventures, The Paul G. Allen Family Foundation, the Engman Foundation, the Ben and Wanda Hildyard Chair in Hereditary Diseases.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Salk Institute Campus

    Every cure has a starting point. Like Dr. Jonas Salk when he conquered polio, Salk scientists are dedicated to innovative biological research. Exploring the molecular basis of diseases makes curing them more likely. In an outstanding and unique environment we gather the foremost scientific minds in the world and give them the freedom to work collaboratively and think creatively. For over 50 years this wide-ranging scientific inquiry has yielded life-changing discoveries impacting human health. We are home to Nobel Laureates and members of the National Academy of Sciences who train and mentor the next generation of international scientists. We lead biological research. We prize discovery. Salk is where cures begin.

     
  • richardmitnick 8:46 am on January 21, 2017 Permalink | Reply
    Tags: , , , Pancreatic tumors rely on signals from surrounding cells, Salk Institute   

    From SALK: “Pancreatic tumors rely on signals from surrounding cells” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    January 19, 2017

    Salk scientists find that targeting the interaction between a pancreatic tumor and its microenvironment could weaken cancer.

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    Tumor cells stained with a marker for cancer (green) appear near stromal cells (red). Credit: Salk Institute.

    Just as an invasive weed might need nutrient-rich soil and water to grow, many cancers rely on the right surroundings in the body to thrive. A tumor’s microenvironment—the nearby tissues, immune cells, blood vessels and extracellular matrix—has long been known to play a role in the tumor’s growth.

    Now, Salk scientists have pinned down how signals from this microenvironment encourage pancreatic tumors to grow by altering their metabolism. Blocking the pathways involved, they reported in Proceedings of the National Academy of Sciences the week of January 16, 2017, can slow the growth of a pancreatic cancer.

    “Pancreatic cancer is a deadly disease and is very understudied when it comes to how it communicates with the microenvironment,” says senior author Ronald Evans, director of Salk’s Gene Expression Laboratory, a Howard Hughes Medical Institute investigator and holder of the March of Dimes Chair in Molecular and Developmental Biology. “Our findings open up a lot of avenues for future study.”

    Pancreatic cancer has the worst five-year survival rate of any major cancer and is expected to be the second leading cause of cancer deaths by the year 2030. It’s notoriously resistant to both chemotherapies and emerging immunotherapies, Evans says, emphasizing the importance of new treatment paradigms.

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    A marker for cancer (green) appears near stomal cells (red) in tumor cells. Credit: Salk Institute.

    Previous research has shown that the signals coming from surrounding stromal cells include both supportive signals—which help pancreatic tumors grow—and suppressive signals—which try to fight the cancer. To understand specifically how pancreatic cancer cells take advantage of any supportive signals, Evans’s team first had to come up with a method to mimic how pancreatic cancer cells grow so closely integrated with the stroma.

    “We worked out a culture system so that we could grow human pancreatic cells in a three-dimensional system in both the presence and absense of stromal signals,” says first author Mara Sherman, a former Salk postdoctoral research fellow now at Oregon Health & Science University.

    When stromal signaling molecules—isolated from patients or generated in the lab—were present, the metabolism of pancreatic cancer cells changed, the researchers found. Not only were levels of metabolic compounds different, but the expression of certain genes involved in metabolism was turned up, and the epigenome of the cells—molecular markers on DNA that change gene expression on a broader scale—was altered.

    “The tumor is essentially hacking into that stromal microenvironment and grabbing what it needs to up its metabolism,” says Michael Downes, a Salk senior scientist involved in the research.

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    From left: Ronald Evans, Mara Sherman, Ruth Yu, Ann Atkins, Tiffany Tseng and Michael Downes. Credit: Salk Institute.

    To try to block this “hacking” of the microenvironment by the cancer cells, the team turned to a drug called JQ1, which is known to block the epigenome changes that they’d observed. Indeed, when JQ1 was added to the 3D culture system, it reversed the genetic changes to the pancreatic cancer cells that the stromal signals had caused. Moreover, when mice with pancreatic tumors were treated with JQ1, tumor growth was slowed.

    More work is needed to reveal whether JQ1, or similar compounds, can shrink or slow the growth of pancreatic tumors in humans and what other pathways in the cancer cells may be responding to the tumor microenvironment, but the findings pave the way for that research.

    Other researchers on the study were Ruth T. Yu, Tiffany W. Tseng, Sihao Liu, Morgan Truitt, Nanhai He, Ning Ding, Annette Atkins, and Mathias Leblanc of the Salk Institute; Cristovao Sousa of Harvard Medical School; Christopher Liddle of the University of Sydney; Eric Collisson of the University of California, San Francisco; John Asara of Beth Israel Deaconess Medical Center; and Alec Kimmelman of the Dana-Farmer Cancer Institute.

    The work and the researchers involved were supported by grants from the National Institutes of Health, the Glenn Foundation for Medical Research, the Leona M. and Harry B. Helmsley Charitable Trust, and Ipsen/Biomeasure.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Salk Institute Campus

    Every cure has a starting point. Like Dr. Jonas Salk when he conquered polio, Salk scientists are dedicated to innovative biological research. Exploring the molecular basis of diseases makes curing them more likely. In an outstanding and unique environment we gather the foremost scientific minds in the world and give them the freedom to work collaboratively and think creatively. For over 50 years this wide-ranging scientific inquiry has yielded life-changing discoveries impacting human health. We are home to Nobel Laureates and members of the National Academy of Sciences who train and mentor the next generation of international scientists. We lead biological research. We prize discovery. Salk is where cures begin.

     
  • richardmitnick 8:59 pm on September 12, 2016 Permalink | Reply
    Tags: , , Salk Institute   

    From Salk: “The brain’s stunning genomic diversity revealed” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    September 9, 2016
    No writer credit found

    Multi-institutional collaboration led by the Salk Institute shows that half of our healthy neurons contain huge insertions or deletions in DNA

    1
    Using postmortem human brains and human embryonic stem cell models of brain development, Salk Institute researchers discover a new mechanism to generate DNA variation in human neurons. Here, human embryonic cell- derived neurons stained for a neurons specific marker (Tuj1, green, DNA show in red) show remarkable diversity. No image credit.

    Our brains contain a surprising diversity of DNA. Even though we are taught that every cell in our body has the same DNA, in fact most cells in the brain have changes to their DNA that make each neuron a little different.

    Now researchers at the Salk Institute and their collaborators have shown that one source of this variation—called long interspersed nuclear elements or L1s—are present in 44 to 63 percent of healthy neurons and can not only insert DNA but also remove it. Previously, these L1s were known to be small bits of DNA called “jumping genes” that copy and paste themselves throughout the genome, but the researchers found that they also cause large deletions of entire genes. What’s more, such variations can influence the expression of genes that are crucial for the developing brain.

    The findings, published September 12, 2016 in the journal Nature Neuroscience, may help explain what makes us each unique—why even identical twins can be so different from one other, for example—and how jumping genes can go awry and cause disease.

    “In 2013, we discovered that different neurons within the same brain have various complements of DNA, suggesting that they function slightly differently from each other even within the same person,” says the study’s senior investigator Rusty Gage, a professor in Salk’s Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases. “This recent study reveals a new and surprising form of variation that will help us understand the role of L1s, not only in healthy brains but in those affected by schizophrenia and autism.”

    In 2005, Gage’s team discovered L1s as a mechanism of genome diversity in the brain. However, it was not until it became possible to sequence the entire genome of a single cell that scientists could get a handle on the amount and nature of these variations. Using single-cell sequencing detailed in a 2013 Science paper, Gage’s group showed that large chunks of DNA were inserted—or deleted—into the genomes of the cells.

    2
    The “jumping gene” L1 cuts DNA in human cells to generate neuronal genomic diversity. Cells expressing L1 (genomic DNA shown in red) have high levels of DNA breaks as visualized by 53BP1 staining (green) which repairs broken DNA. Credit: Salk Institute

    But even in that study the mechanisms responsible for causing insertions and deletions were unclear, making it difficult to decipher whether specific regions of the genome were more or less likely to be altered, as well as whether jumping genes were related to the deletions.

    In the new study, Gage, co-first authors Jennifer Erwin and Apuã Paquola, and collaborators developed a method to better capture the L1-associated variants in healthy neurons for sequencing and created a computational algorithm to distinguish the variations with greater accuracy than before.

    Using stem cells that are coaxed to differentiate into neurons in a dish, the team found that L1s are prone to DNA breaks. That’s because a specific enzyme that chews through L1 spots in the genome is particularly active during differentiation. People inherit some L1s from their parents, and the enzyme appears to cut near these spots, the group found.

    “The surprising part was that we thought all L1s could do was insert into new places. But the fact that they’re causing deletions means that they’re affecting the genome in a more significant way,” says Erwin, a staff scientist in Gage’s group.

    Gage believes that diversity can be good for the brain—after all, about half of our brain cells have large chunks of missing or inserted DNA caused by L1s alone—but that too much of it can cause disease.

    Recent evidence has shown that neurons derived from individuals with schizophrenia or the rare autism-associated disorder Rett syndrome harbor more than normal amounts of L1 variations in their genomes. In the new study, the team examined a schizophrenia-associated gene called DLG2, in which introducing L1 variations can change the gene’s expression and subsequent maturation of neurons. The group plans to explore the role of L1 variations in other genes and their effects on brain activity and disease.

    Other authors on the study are Tatjana Singer, Iryna Gallina, Carolina Quayle, Tracy Bedrosian, Cheyenne Butcher, Joseph Herdy and Anindita Sarkar of Salk; Mark Novotny and Roger Lasken of the J. Craig Venter Institute; Francisco Alves of the University of São Paulo in Brazil; and Alysson Muotri of the University of California, San Diego.

    The research was supported by George E. Hewitt Foundation for Medical Research, the California Institute for Regenerative Medicine, the National Institutes of Health (MH095741, MH088485), the G. Harold & Leila Y. Mathers Foundation, the Engman Foundation, the Leona M. and Harry B. Helmsley Charitable Trust, the Paul G. Allen Family Foundation, the Glenn Center for Aging Research at the Salk Institute, and JPB Foundation.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Salk Institute Campus

    Every cure has a starting point. Like Dr. Jonas Salk when he conquered polio, Salk scientists are dedicated to innovative biological research. Exploring the molecular basis of diseases makes curing them more likely. In an outstanding and unique environment we gather the foremost scientific minds in the world and give them the freedom to work collaboratively and think creatively. For over 50 years this wide-ranging scientific inquiry has yielded life-changing discoveries impacting human health. We are home to Nobel Laureates and members of the National Academy of Sciences who train and mentor the next generation of international scientists. We lead biological research. We prize discovery. Salk is where cures begin.

     
  • richardmitnick 1:42 pm on August 31, 2016 Permalink | Reply
    Tags: , , , Salk Institute, Unravel bipolar disorder and schizophrenia   

    From Salk: “Johns Hopkins and Salk co-lead $15 million initiative to unravel bipolar disorder and schizophrenia” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    August 31, 2016
    No writer credit found

    Partnership of government, academics and industry will develop new ways of studying and screening drugs for major psychiatric illnesses.

    The Johns Hopkins University School of Medicine and the Salk Institute for Biological Studies will co-lead a $15.4 million effort to develop new systems for quickly screening libraries of drugs for potential effectiveness against schizophrenia and bipolar disorder, the National Institute of Mental Health (NIMH) has announced. The consortium, which includes four academic or nonprofit institutions and two industry partners, will be led by Hongjun Song, PhD, of Johns Hopkins and Rusty Gage, PhD, of Salk.

    Bipolar disorder affects more than 5 million Americans, and treatments often help only the depressive swings or the opposing manic swings, not both. And though schizophrenia is a devastating disease that affects about 3 million Americans and many more worldwide, scientists still know very little about its underlying causes—which cells in the brain are affected and how—and existing treatments target symptoms only.

    With the recent advance of induced pluripotent stem cell (iPSC) technology, researchers are able to use donated cells, such as skin cells, from a patient and convert them into any other cell type, such as neurons. Generating human neurons in a dish that are genetically similar to patients offers researchers a potent tool for studying these diseases and developing much-needed new therapies.

    A major aim of this collaboration is to improve the quality of iPSC technology, which has been limited in the past by a lack of standards in the field and inconsistent practices among different laboratories. “There has been a bottleneck in stem cell research,” says Song, a professor of neurology and neuroscience at Johns Hopkins. “Every lab uses different protocols and cells from different patients, so it’s really hard to compare results. This collaboration gathers the resources needed to create robust, reproducible tests that can be used to develop new drugs for mental health disorders.”

    “IPSCs are a powerful platform for studying the underlying mechanisms of disease,” says Gage, a professor of genetics at Salk. “Collaborations that bring together academic and industry partners, such as this one enabled by NIMH, will greatly facilitate the improvement of iPSC approaches for high-throughput diagnostic and drug discovery.”

    The teams will use iPSCs generated from more than 50 patients with schizophrenia or bipolar disorder so that a wide range of genetic differences is taken into account. By coaxing iPSCs to become four different types of brain cells, the teams will be able to see which types are most affected by specific genetic differences and when those effects may occur during development.

    First the researchers must figure out, at the cellular level, what features characterize a given illness in a given brain cell type. To do that, they will assess the cells’ shapes, connections, energy use, division and other properties. They will then develop a way of measuring those characteristics that works on a large scale, such as recording the activity of cells under hundreds of different conditions simultaneously.

    Once a reliable, scalable and reproducible test system has been developed, the industry partners will have the opportunity to use it to identify or develop drugs that might combat mental illness. “This exciting new research has great potential to expedite drug discovery by using human cells from individuals who suffer from these devastating illnesses. Starting with a deeper understanding of each disorder should enable the biopharmaceutical industry to design drug discovery strategies that are focused on molecular pathology,” says Husseini K. Manji, M.D., F.R.C.P.C., global therapeutic area head of neuroscience for Janssen Research & Development.

    The researchers also expect to develop a large body of data that will shed light on the molecular and genetic differences between bipolar disorder and schizophrenia. And, since other mental health disorders share some of the genetic variations found in schizophrenia and bipolar disorder, the data will likely inform the study of many illnesses.

    The National Cooperative Reprogrammed Cell Research Groups program, which is funding the research, was introduced by the National Institute of Mental Health in 2013 to overcome barriers to collaboration by creating precompetitive agreements that harness the unique strengths of academic and industry research. The federal-academic-industry collaboration will bring together leading experts in the fields of stem cells and neuropsychiatric disorders:

    Academic Partners:

    Hongjun Song, Professor, the Johns Hopkins University School of Medicine
    Rusty Gage, Professor, Laboratory of Genetics at the Salk Institute
    Sue O’Shea, Director, Michigan Pluripotent Stem Cell Core and Professor, University of Michigan
    Anne Bang, Director, Conrad Prebys Center for Chemical Genomics at the Sanford Burnham Prebys Medical Discovery Institute

    Industry Partners:

    Guang Chen, Janssen fellow, Scientific Director of Neuroscience, Janssen Research & Development
    Jeffrey S. Nye, Vice President, Neuroscience Innovation and Partnership Strategy, Janssen Research & Development, J&J Innovation
    Husseini K. Manji, Global Therapeutic Area Head of Neuroscience, Janssen Research & Development
    Paul Doran, Strategic Alliance Manager, Cellular Dynamics International

    Funding Announcement: http://grants.nih.gov/grants/guide/pa-files/PAR-13-225.html
    Supported by NIMH Cooperative Agreement Number U19MH106434

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Salk Institute Campus

    Every cure has a starting point. Like Dr. Jonas Salk when he conquered polio, Salk scientists are dedicated to innovative biological research. Exploring the molecular basis of diseases makes curing them more likely. In an outstanding and unique environment we gather the foremost scientific minds in the world and give them the freedom to work collaboratively and think creatively. For over 50 years this wide-ranging scientific inquiry has yielded life-changing discoveries impacting human health. We are home to Nobel Laureates and members of the National Academy of Sciences who train and mentor the next generation of international scientists. We lead biological research. We prize discovery. Salk is where cures begin.

     
  • richardmitnick 5:25 pm on August 25, 2016 Permalink | Reply
    Tags: , , Salk Institute   

    From Salk: “Salk scientists map brain’s action center” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    August 25, 2016
    No writer credit found

    New work dispels long-held notions about area involved in Parkinson’s and addiction

    1
    Salk Institute researchers employed novel genetic tools to map the connectivity of neurons within a part of the brain, called the striatum, that controls movement toward a goal or reward. The matrix neurons, highlighted in green, appear to avoid the patch neurons (in red), which are smaller clusters of neurons in the striatum. Credit: Salk Institute

    When you reach for that pan of brownies, a ball-shaped brain structure called the striatum is critical for controlling your movement toward the reward. A healthy striatum also helps you stop yourself when you’ve had enough.

    But when the striatum doesn’t function properly, it can lead to disorders such as Parkinson’s disease, obsessive-compulsive disorder or addiction.

    In fact, the exact functions of the striatum are by no means resolved, and it’s also a mystery how the structure can coordinate many diverse functions. Now, a new study published August 25, 2016 by Salk Institute researchers and their colleagues in the journal Neuron, delves into the anatomy and function of the striatum by employing cutting-edge strategies to comprehensively map one of the brain’s lesser-known forms of organization.

    “The most exciting result from this research is that we now have a new avenue to study long-standing questions about how the striatum controls movement in both healthy and diseased brains,” says the study’s senior investigator Xin Jin, an assistant professor in the Molecular Neurobiology Laboratory at Salk.

    Forty years ago, researchers discovered a unique way that the striatum is organized. It is dotted with patch neurons, which under the microscope look like tiny islands of cells. The ocean surrounding them is made up of neurons scientists collectively refer to as “matrix” cells.

    Over the course of four decades, scientists hypothesized about the role of patch and matrix neurons in neurodegenerative diseases. One idea was that patch cells were fed by the brain’s higher thought centers, suggesting they could play a role in cognition, whereas the matrix cells seemed to play a role in sensing and movement.

    2
    Using genetic engineering, cutting-edge neuronal tracing and electrophysiology, researchers decipher a lesser known form of organization in a deep, ball-shaped brain area that helps control movement toward a goal. In this artistic interpretation, patch neurons (red) sit as separate, small islands amid matrix neurons (green), but each cell type is well connected with the rest of the brain. Credit: Salk Institute

    In contrast, the new study dispels that idea, showing that both types of information are sent to the patch and matrix neurons, though patch cells tend to receive slightly more information from the brain’s emotion centers (these are included in the higher thought centers). But those results could help explain why, in the brains of patients with neurological disorders like Huntington’s disease (a progressive neurodegenerative disease affecting movement and other functions), patch cells and matrix cells are both affected, Jin says.

    “This is an elegant example demonstrating that we are in a new era of studying brain circuits in ever more refined detail,” said Daofen Chen, Ph.D., program director at the NIH’s National Institute of Neurological Disorders and Stroke. “As a result of emerging technologies and novel tools, we are gaining new insights into mechanisms of brain disorders.”

    Jin, together with the paper’s first authors Jared Smith, Jason Klug and Danica Ross, drew upon several technologies to uncover these new findings. The first was genetic engineering to selectively and precisely target the patch versus matrix neurons; traditionally, researchers used staining methods that were not as exact. Secondly, new neural tracing methods, including one generated by collaborator Edward Callaway and his group at Salk, allowed Jin’s team to chart the entire brain’s input to the patch and matrix cells and the output of each of the cell types as well. A third major approach, from the field of electrophysiology, enabled the scientists to confirm the connections they had mapped and to understand their strength.

    “Much of the previous work on patch and matrix cells inferred their functions based on connectivity with the rest of the brain, but most of those hypotheses were incorrect,” Smith says. “With a more precise map of the input and output of patch and matrix cells, we can now make more informed hypotheses.”

    Patch and matrix neurons are not the only way that neuroscientists understand the striatum. The striatum also contains cells that take two opposing routes—the direct and indirect pathways—that are thought to provide the gas and brakes on movement, so to speak. Those indirect and direct pathways are also crucial for certain behaviors, such as the formation of new habits.

    Interestingly, both patch and matrix groups contain both indirect and direct pathway cells. That makes the story of the striatum more complicated, Jin says, but in future studies his team can study the intersection of these two types of organization in the context of how the striatum controls actions in health and disease.

    Other authors on the study are Jason Klug, Danica Ross, Christopher Howard, Nick Hollon, Vivian Ko, Hilary Hoffman and Edward Callaway of the Salk Institute; and Charles Gerfen of the National Institute of Mental Health in Bethesda, Maryland.

    The research was supported by grants from the National Institutes of Health, the Dana Foundation, the Ellison Medical Foundation, and the Whitehall Foundation.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Salk Institute Campus

    Every cure has a starting point. Like Dr. Jonas Salk when he conquered polio, Salk scientists are dedicated to innovative biological research. Exploring the molecular basis of diseases makes curing them more likely. In an outstanding and unique environment we gather the foremost scientific minds in the world and give them the freedom to work collaboratively and think creatively. For over 50 years this wide-ranging scientific inquiry has yielded life-changing discoveries impacting human health. We are home to Nobel Laureates and members of the National Academy of Sciences who train and mentor the next generation of international scientists. We lead biological research. We prize discovery. Salk is where cures begin.

     
  • richardmitnick 1:38 pm on August 25, 2016 Permalink | Reply
    Tags: , , Neuregulin-1, Salk Institute   

    From Salk: “Elevating brain protein allays symptoms of Alzheimer’s and improves memory” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    August 25, 2016
    No writer credit found

    Salk Institute tests drug that could boost levels of critical protective protein in brain

    1
    In a mouse model of Alzheimer’s disease, Salk Institute researchers show that raising levels of neuregulin-1 (right) lowers a marker of disease pathology in a part of the brain that controls memory compared with controls (left). Credit: Salk Institute

    LA JOLLA—Boosting levels of a specific protein in the brain alleviates hallmark features of Alzheimer’s disease in a mouse model of the disorder, according to new research published online August 25, 2016 in Scientific Reports.

    The protein, called neuregulin-1, has many forms and functions across the brain and is already a potential target for brain disorders such as Parkinson’s disease, amyotrophic lateral sclerosis and schizophrenia.

    “Neuregulin-1 has broad therapeutic potential, but mechanistically, we are still learning about how it works,” says the study’s senior investigator Kuo-Fen Lee, a professor in the Salk Institute’s Clayton Foundation Laboratories for Peptide Biology and holder of the Helen McLoraine Chair in Molecular Neurobiology. “We’ve shown that it promotes metabolism of the brain plaques that are characteristic of Alzheimer’s disease.”

    Previously, researchers have shown that treating cells with neuregulin-1, for example, dampens levels of amyloid precursor protein, a molecule that generates amyloid beta, which aggregate and form plaques in the brains of Alzheimer’s patients. Other studies suggest that neuregulin-1 could protect neurons from damage caused by blockage of blood flow.

    In the new study, Lee’s team tested this idea in a mouse model of Alzheimer’s disease by raising the levels of one of two forms of neuregulin-1 in the hippocampus, an area of the brain responsible for learning and memory. Both forms of the protein seemed to improve performance on a test of spatial memory in the models.

    What’s more, the levels of cellular markers of disease—including the levels of amyloid beta and plaques—were noticeably lower in mice with more neuregulin-1 compared to controls.

    The group’s experiments suggest that neuregulin-1 breaks up plaques by raising levels of an enzyme called neprilysin, shown to degrade amyloid-beta. But that is probably not the only route through which neuregulin-1 confers its benefits, and the group is exploring other possible mechanisms—such as whether the protein improves signaling between neurons, which is impaired in Alzheimer’s—says the study’s first author Jiqing Xu, a research associate in Lee’s group

    A neuregulin-1 treatment is not available on the market, though it is being explored in clinical trials as a potential treatment for chronic heart failure and Parkinson’s disease. One advantage of neuregulin-1 as a potential drug is that it can cross the blood brain barrier, which means that it could be administered relatively noninvasively even though the efficiency is not clear. On the other hand, other research suggests too much of the protein impairs brain function. Working with chemists at Salk, Lee’s team has come up with a small molecule that can raise levels of existing neuregulin-1 (rather than administering it directly) and are testing it in cells. This alternative therapy could be a better way to prevent plaques from forming because small molecules more readily cross the blood brain barrier.

    The group is also interested in neuregulin-1 for its ties to schizophrenia. An alteration in the neuregulin-1 gene—a single change in one letter of the DNA code for the protein—has been found in families with schizophrenia and linked to late-onset Alzheimer’s disease with psychosis. The protein may be a way to understand the overlap between Alzheimer’s and other brain disorders, Lee says.

    An important caveat is that the new research was conducted in a single type of mouse model of Alzheimer’s. Lee’s group is testing neuregulin-1’s affects across other models. “There’s much more work ahead before neuregulin-1 could become a treatment, but we are excited about its potential, possibly in combination with other therapeutics for Alzheimer’s disease,” Lee says.

    Other authors on the study are Fred DeWinter, Catherine Farrokhi, Jonathan Cook and Xin Jin of Salk’s Clayton Foundation for Peptide Biology Laboratories; and Edward Rockenstein, Michael Mante, Anthony Adame and Eliezer Masliah of the University of California, San Diego.

    The research was supported by the National Institutes of Health, the Clayton Foundation, The Albert G. and Olive H. Schlink Foundation, the Gemcon Family Foundation and the Brown Foundation.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Salk Institute Campus

    Every cure has a starting point. Like Dr. Jonas Salk when he conquered polio, Salk scientists are dedicated to innovative biological research. Exploring the molecular basis of diseases makes curing them more likely. In an outstanding and unique environment we gather the foremost scientific minds in the world and give them the freedom to work collaboratively and think creatively. For over 50 years this wide-ranging scientific inquiry has yielded life-changing discoveries impacting human health. We are home to Nobel Laureates and members of the National Academy of Sciences who train and mentor the next generation of international scientists. We lead biological research. We prize discovery. Salk is where cures begin.

     
  • richardmitnick 2:49 pm on August 15, 2016 Permalink | Reply
    Tags: , Disregarded plant molecule actually a treasure, Phaseic acid, Salk Institute   

    From Salk: “Disregarded plant molecule actually a treasure” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    August 11, 2016

    The best natural chemists out there are not scientists—they’re plants. Plants have continued to evolve a rich palette of small natural chemicals and receptors since they began to inhabit land roughly 450 million years ago.

    Now, research by Salk Institute scientists published August 11, 2016 in the journal Cell reveals an unexpected role for a small, often overlooked molecule called phaseic acid, which has historically been cast as an inactive byproduct in plants—a metabolic dead end of sorts. The new findings suggest that phaseic acid and its receptors probably co-evolved to become crucial for drought resistance and other survival traits and may inform the development of new, hardier crops that can weather natural disasters wrought by climate change.

    1
    Seed plants evolved a dedicated enzyme to degrade phaseic acid and keep its level in check. A plant lacking this enzyme accumulates more phaseic acid, and is more resistant to long-term drought conditions (right) compared with a normal plant (left). Credit: Salk Institute

    “There had been some hints that phaseic acid was not just an inactive bystander but a plant hormone with an important role,” says the study’s senior investigator Joseph Noel, holder of the Arthur and Julie Woodrow Chair and professor in the Jack H. Skirball Center for Chemical Biology and Proteomics at Salk. “But now, by using an array of cutting-edge biological approaches, we’ve shown more convincingly, that phaseic acid is likely important for survival.”

    Phaseic acid has long lived in the shadows of its precursor—abscisic acid or ABA—which is a big deal in plant research. ABA is a plant hormone that’s present in all land plants and is key for responding to environmental stress and pathogens, in particular alerting the plant to drought conditions. ABA is also known for its connection to the good stuff in fruits and vegetables: carotenoids, such as beta-carotene and lycopene.

    Like all small natural molecules, ABA is produced through intricate metabolic pathways that transform simple carbon-based building blocks into structurally complex natural chemicals that collectively convey a substantial amount of information. Some plants are equipped with more than a handful of receptors for ABA, each of which carries out various functions in the plant. But paradoxically for its role as a master regulator, ABA itself seemed have equal preference for all its receptors, which would not be ideal for the fine-tuned control of plant function.

    In the new study, Noel’s team used a commonly studied plant called Arabidopsis thaliana and obtained varieties that lacked the enzyme that processes phaseic acid, in effect accumulating large amounts of phaseic acid.

    To the group’s surprise, the plants showed changes to the timing of seed germination and they survived without water for a longer time period. “This suggested to us that maybe we should be thinking of phaseic acid not as an inactive degradation product but actually as a molecule that had its own capacity to cause changes like other plant hormones,” says Noel.

    2
    The enzyme that degrades phaseic acid (blue) appears briefly in response to light during early seed germination. The picture on the left was taken one day after plant seeds were taken from a dark environment to light; the picture on the right was taken on the second day. Credit: Salk Institute

    The scientists carried out a series of studies pointing to phaseic acid’s role as a plant hormone, showing for example that the addition of phaseic acid to normal seedlings triggered changes to the expression of numerous specific genes, especially genes coding for metabolic enzymes, that were overlapping but also distinct from those activated by ABA.

    In addition, using a high-resolution imaging technique called x-ray crystallography, the group showed that phaseic acid bound to ABA’s receptors, solidifying evidence that ABA’s receptors can sense more than just ABA.

    The new study suggests more broadly that there could be more hidden complexity to how organisms make use of small chemicals to bring about a variety of different responses. Evolution may well have repurposed other so-called end products of metabolism, Noel says.

    The study’s first author, Jing-Ke Weng, formerly a postdoctoral researcher in Noel’s lab, has set up an independent research group within Massachusetts Institute of Technology’s Whitehead Institute for Biomedical Research and Department of Biology that will continue to explore plant chemicals with previously unappreciated roles. “We hope to discover and understand the complexity of the hormones’, their metabolites and their collective interplay with receptors in various plants,” says Weng.

    Noel’s team will study the role of the hormones in the roots of plants. There is evidence that the phaseic acid and ABA play a role in moving carbon from a plant’s leaves and stems into its roots to protect them during periods of drought, overwintering and during pathogen attacks in the soil, Noel says. “Understanding this area of plant biology offers new ways to think about how we might mitigate climate change.”

    This research was supported by the National Science Foundation, the Pioneer Foundation, the Pew Charitable Trusts, the Searle Scholars Program and the Howard Hughes Medical Institute.

    Other authors on the study are Mingli Ye of the Salk Institute and Bin Li of the University of California, San Diego School of Medicine.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Salk Institute Campus

    Every cure has a starting point. Like Dr. Jonas Salk when he conquered polio, Salk scientists are dedicated to innovative biological research. Exploring the molecular basis of diseases makes curing them more likely. In an outstanding and unique environment we gather the foremost scientific minds in the world and give them the freedom to work collaboratively and think creatively. For over 50 years this wide-ranging scientific inquiry has yielded life-changing discoveries impacting human health. We are home to Nobel Laureates and members of the National Academy of Sciences who train and mentor the next generation of international scientists. We lead biological research. We prize discovery. Salk is where cures begin.

     
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