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  • richardmitnick 8:44 am on August 3, 2017 Permalink | Reply
    Tags: , , , , Salk Institute   

    From Salk: “Early gene-editing success holds promise for preventing inherited diseases” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    August 2, 2017

    Scientists have, for the first time, corrected a disease-causing mutation in early stage human embryos with gene editing. The technique, which uses the CRISPR-Cas9 system, corrected the mutation for a heart condition at the earliest stage of embryonic development so that the defect would not be passed on to future generations.

    The work, which is described in Nature on August 2, 2017, is a collaboration between the Salk Institute, Oregon Health and Science University (OHSU) and Korea’s Institute for Basic Science and could pave the way for improved in vitro fertilization (IVF) outcomes as well as eventual cures for some of the thousands of diseases caused by mutations in single genes.

    “Thanks to advances in stem cell technologies and gene editing, we are finally starting to address disease-causing mutations that impact potentially millions of people,” says Juan Carlos Izpisua Belmonte, a professor in Salk’s Gene Expression Laboratory and a corresponding author of the paper. “Gene editing is still in its infancy so even though this preliminary effort was found to be safe and effective, it is crucial that we continue to proceed with the utmost caution, paying the highest attention to ethical considerations.”

    Though gene-editing tools have the power to potentially cure a number of diseases, scientists have proceeded cautiously, in part to avoid introducing unintended mutations into the germ line (cells that become eggs or sperm). Izpisua Belmonte is uniquely qualified to speak to the ethics of genome editing in part because, as a member of the committee on human gene editing of the National Academies of Sciences, Engineering and Medicine, he helped author the 2016 roadmap “Human Genome Editing: Science, Ethics, and Governance.” The research in the current study is fully compliant with recommendations made in that document, and adheres closely to guidelines established by OHSU’s Institutional Review Board and additional ad-hoc committees set up for scientific and ethical review.

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    Newly fertilized eggs before gene editing (left) and embryos after gene editing and a few rounds of cell division (right). Credit: OHSU/Mitalipov lab.

    Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden death in otherwise healthy young athletes, and affects approximately 1 in 500 people overall. It is caused by a dominant mutation in the MYBPC3 gene, but often goes undetected until it is too late. Since people with a mutant copy of the MYBPC3 gene have a 50 percent chance of passing it on to their own children, being able to correct the mutation in embryos would prevent the disease not only in affected children, but also in their descendants.

    The researchers generated induced pluripotent stem cells from a skin biopsy donated by a male with HCM and developed a gene-editing strategy based on CRISPR-Cas9 that would specifically target the mutated copy of the MYBPC3 gene for repair. The targeted mutated MYBPC3 gene was cut by the Cas9 enzyme, allowing the donor’s cells’ own DNA-repair mechanisms to fix the mutation during the next round of cell division by using either a synthetic DNA sequence or the non-mutated copy of MYBPC3 gene as a template.

    Using IVF techniques, the researchers injected the best-performing gene-editing components into healthy donor eggs newly fertilized with the donor’s sperm. Then they analyzed all the cells in the early embryos at single-cell resolution to see how effectively the mutation was repaired.

    The scientists were surprised by just how safe and efficient the method was. Not only did a high percentage of embryonic cells get repaired, but also gene correction didn’t induce any detectable off-target mutations and genome instability—major concerns for gene editing. In addition, the researchers developed a robust strategy to ensure the repair occurred consistently in all the cells of the embryo. (Spotty repairs can lead to some cells continuing to carry the mutation.)

    “Even though the success rate in patient cells cultured in a dish was low, we saw that the gene correction seems to be very robust in embryos of which one copy of the MYBPC3 gene is mutated,” says Jun Wu, a Salk staff scientist and one of the paper’s first authors. This was in part because, after CRISPR-Cas9 mediated enzymatic cutting of the mutated gene copy, the embryo initiated its own repairs. Instead of using the provided synthetic DNA template, the team found, surprisingly, that the embryo preferentially used the available healthy copy of the gene to repair the mutated part. “Our technology successfully repairs the disease-causing gene mutation by taking advantage of a DNA repair response unique to early embryos” says Wu.

    Izpisua Belmonte and Wu emphasize that, although promising, these are very preliminary results and more research will need to be done to ensure no unintended effects occur.

    “Our results demonstrate the great potential of embryonic gene editing, but we must continue to realistically assess the risks as well as the benefits,” adds Izpisua Belmonte.

    Future work will continue to assess the safety and effectiveness of the procedure and efficacy of the technique with other mutations.

    Other authors included: Keiichiro Suzuki of the Salk Institute; Hong Ma, Nuria Marti-Gutierrez, Yeonmi Lee, Amy Koski, Dongmei Ji, Tomonari Hayama, Riffat Ahmed, Hayley Darby, Crystal Van Dyken, Ying Li, Eunju Kang, David Battaglia, Sacha A. Krieg, David M. Lee, Diana H. Wu, Don P. Wolf, Stephen B. Heitner, Paula Amato, Sanjiv Kaul and Shoukhrat Mitalipov of Oregon Health and Science University; Sang-Wook Park, A-Reum Park, Sang-Tae Kim and Jin-Soo Kim of Korea’s Institute for Basic Science; Daesik Kim of Seoul National University; and Jianhui Gong, Ying Gu and Xun Xu of BGI, China.

    The work was funded by: Oregon Health and Science University, the Institute for Basic Science, the G. Harold and Leila Y. Mathers Charitable Foundation, the Moxie Foundation, the Leona M. and Harry B. Helmsley Charitable Trust, and Shenzhen Municipal Government of China.

    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 11:53 am on July 29, 2017 Permalink | Reply
    Tags: 3D structure of human chromatin, , ChromEMT, , , , , , Salk Institute   

    From Salk: “Salk scientists solve longstanding biological mystery of DNA organization” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    July 27, 2017

    Stretched out, the DNA from all the cells in our body would reach Pluto. So how does each tiny cell pack a two-meter length of DNA into its nucleus, which is just one-thousandth of a millimeter across?

    The answer to this daunting biological riddle is central to understanding how the three-dimensional organization of DNA in the nucleus influences our biology, from how our genome orchestrates our cellular activity to how genes are passed from parents to children.

    Now, scientists at the Salk Institute and the University of California, San Diego, have for the first time provided an unprecedented view of the 3D structure of human chromatin—the combination of DNA and proteins—in the nucleus of living human cells.

    In the tour de force study, described in Science on July 27, 2017, the Salk researchers identified a novel DNA dye that, when paired with advanced microscopy in a combined technology called ChromEMT, allows highly detailed visualization of chromatin structure in cells in the resting and mitotic (dividing) stages. By revealing nuclear chromatin structure in living cells, the work may help rewrite the textbook model of DNA organization and even change how we approach treatments for disease.

    “One of the most intractable challenges in biology is to discover the higher-order structure of DNA in the nucleus and how is this linked to its functions in the genome,” says Salk Associate Professor Clodagh O’Shea, a Howard Hughes Medical Institute Faculty Scholar and senior author of the paper. “It is of eminent importance, for this is the biologically relevant structure of DNA that determines both gene function and activity.”

    2
    A new technique enables 3D visualization of chromatin (DNA plus associated proteins) structure and organization within a cell nucleus (purple, bottom left) by painting the chromatin with a metal cast and imaging it with electron microscopy (EM). The middle block shows the captured EM image data, the front block illustrates the chromatin organization from the EM data, and the rear block shows the contour lines of chromatin density from sparse (cyan and green) to dense (orange and red). Credit: Salk Institute.

    Ever since Francis Crick and James Watson determined the primary structure of DNA to be a double helix, scientists have wondered how DNA is further organized to allow its entire length to pack into the nucleus such that the cell’s copying machinery can access it at different points in the cell’s cycle of activity. X-rays and microscopy showed that the primary level of chromatin organization involves 147 bases of DNA spooling around proteins to form particles approximately 11 nanometers (nm) in diameter called nucleosomes. These nucleosome “beads on a string” are then thought to fold into discrete fibers of increasing diameter (30, 120, 320 nm etc.), until they form chromosomes. The problem is, no one has seen chromatin in these discrete intermediate sizes in cells that have not been broken apart and had their DNA harshly processed, so the textbook model of chromatin’s hierarchical higher-order organization in intact cells has remained unverified.

    To overcome the problem of visualizing chromatin in an intact nucleus, O’Shea’s team screened a number of candidate dyes, eventually finding one that could be precisely manipulated with light to undergo a complex series of chemical reactions that would essentially “paint” the surface of DNA with a metal so that its local structure and 3D polymer organization could be imaged in a living cell. The team partnered with UC San Diego professor and microscopy expert Mark Ellisman, one of the paper’s coauthors, to exploit an advanced form of electron microscopy that tilts samples in an electron beam enabling their 3D structure to be reconstructed. By combining their chromatin dye with electron-microscope tomography, they created ChromEMT.

    The team used ChromEMT to image and measure chromatin in resting human cells and during cell division when DNA is compacted into its most dense form—the 23 pairs of mitotic chromosomes that are the iconic image of the human genome. Surprisingly, they did not see any of the higher-order structures of the textbook model anywhere.

    3
    From left: Horng Ou and Clodagh O’Shea. Credit: Salk Institute.

    “The textbook model is a cartoon illustration for a reason,” says Horng Ou, a Salk research associate and the paper’s first author. “Chromatin that has been extracted from the nucleus and subjected to processing in vitro—in test tubes—may not look like chromatin in an intact cell, so it is tremendously important to be able to see it in vivo.”

    What O’Shea’s team saw, in both resting and dividing cells, was chromatin whose “beads on a string” did not form any higher-order structure like the theorized 30 or 120 or 320 nanometers. Instead, it formed a semi-flexible chain, which they painstakingly measured as varying continuously along its length between just 5 and 24 nanometers, bending and flexing to achieve different levels of compaction. This suggests that it is chromatin’s packing density, and not some higher-order structure, that determines which areas of the genome are active and which are suppressed.

    With their 3D microscopy reconstructions, the team was able to move through a 250 nm x 1000 nm x 1000 nm volume of chromatin’s twists and turns, and envision how a large molecule like RNA polymerase, which transcribes (copies) DNA, might be directed by chromatin’s variable packing density, like a video game aircraft flying through a series of canyons, to a particular spot in the genome. Besides potentially upending the textbook model of DNA organization, the team’s results suggest that controlling access to chromatin could be a useful approach to preventing, diagnosing and treating diseases such as cancer.

    “We show that chromatin does not need to form discrete higher-order structures to fit in the nucleus,” adds O’Shea. “It’s the packing density that could change and limit the accessibility of chromatin, providing a local and global structural basis through which different combinations of DNA sequences, nucleosome variations and modifications could be integrated in the nucleus to exquisitely fine-tune the functional activity and accessibility of our genomes.”

    Future work will examine whether chromatin’s structure is universal among cell types or even among organisms.

    Other authors included Sébastien Phan, Thomas Deerinck and Andrea Thor of the UC San Diego.

    The work was largely funded by the W. M. Keck Foundation, the NIH 4D Nucleome Roadmap Initiative and the Howard Hughes Medical Institute, with additional support from the William Scandling Trust, the Price Family Foundation and the Leona M. and Harry B. Helmsley Charitable Trust.

    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 8:05 am on July 27, 2017 Permalink | Reply
    Tags: , , How plant architectures mimic subway networks, Salk Institute, Using 3D laser scans of growing plants   

    From Salk: “How plant architectures mimic subway networks” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    7.26.17
    Chris Emery
    Kristina Grifantini
    press@salk.edu
    858.453.4100

    Salk scientists use 3D laser scanning to understand how plants optimize their growth.

    1
    Salk Institute scientists find that plants and subway systems are both networks that strive to make similar tradeoffs between cost and performance. Credit: Salk Institute.

    It might seem like a tomato plant and a subway system don’t have much in common, but both, it turns out, are networks that strive to make similar tradeoffs between cost and performance.

    Using 3D laser scans of growing plants, Salk scientists found that the same universal design principles that humans use to engineer networks like subways also guide the shapes of plant branching architectures. The work, which appears in the July 26, 2017, issue of Cell Systems, could help direct strategies to increase crop yields or breed plants better adapted to climate change.

    “The idea for this work really started with an engineering question,” says Saket Navlakha, assistant professor in Salk’s Center for Integrative Biology and senior author of the paper. “How do transportation networks like a subway system or an electric grid resolve the tension between two competing objectives, such as cost and performance? And do plants resolve similar competing objectives in the same way?”

    Engineered transportation networks, whether for moving people or power, need to balance the cost of construction with providing efficient transport. Think of a subway system: If the main objective when designing it is to get people from the suburbs to downtown as quickly as possible, each suburb will have its own direct line to downtown. But that would be prohibitively expensive to build. Conversely, if the only objective is to limit cost, there would be very few lines, and it would take a long time for some riders to reach downtown. Thus, the engineering challenge is to find some balance of these two objectives. If you extend this analogy to a plant, its base is like downtown and its leaves are like the suburbs. Nutrients need to get between these areas as quickly as possible, while limiting the cost of growing extraneous branches.

    In engineering and other fields, tradeoffs such as this can be represented on a graph as a curved line called the Pareto front. Here, one end of the curve represents a very affordable system that has low performance, while the other end represents an expensive system with high performance. Points along the curve represent different ratios of cost to performance. When applying this framework to plants, the team defined cost as the total length of the branches, because it takes energy and resources for the plant to grow them. They defined performance as the sum of distances from the plant’s base to each leaf because this represents how far nutrients (water and sugars) have to travel between the root and leaves.

    To understand how plants might manage the tradeoff between these two objectives, Navlakha’s team began with three agriculturally valuable crops: sorghum, tomato and tobacco. They grew the plants from seeds under conditions the plants might experience naturally (shade, ambient light, high light, high heat and drought). Every few days for 20 days, they digitally scanned each plant to capture its growing network of branches, stems and leaves. In all, they took about 500 scans.

    “Scanning plants in three dimensions can be fairly time consuming,” says Adam Conn, a Salk research assistant and the paper’s first author. “But it’s non-invasive, and once you’ve done it you can discover things from the data that you couldn’t learn by just looking at the plants.”

    From the digital versions of the plants, the team extracted coordinates corresponding to each plant’s base and leaves in 3D space. They used the coordinates to create and graph theoretical plant shapes that prioritize either efficient routes for nutrients (performance), minimal branch length (cost), or various tradeoffs between the two objectives.

    2
    From left: Joanne Chory and Saket Navlakha. Credit: Salk Institute.

    Surprisingly, when they placed the real plants on the graph according to their actual nutrient travel distances and total branch lengths, the plants fell almost perfectly on the Pareto curve, meaning that plants’ networks of branches are finding the best balance between cost and performance for their particular environment.

    “Our hypothesis was that if total length and travel distance were important evolutionary criteria for plants, there would be evolutionary pressure to minimize the criteria together, and that’s actually what we found,” says Ullas Pedmale, who was a postdoctoral researcher on the project and is now an assistant professor at Cold Spring Harbor Laboratory.

    Interestingly, the plants clustered by species, but within each species, plants made different tradeoffs based on their growth environment. In other words, all tomatoes were in generally the same region of the curve, but ones grown in high light found a different balance between cost and performance than ones grown in low light.

    “This means the way plants grow their architectures also optimizes a very common network design tradeoff. Based on the environment and the species, the plant is selecting different ways to make tradeoffs for those particular environmental conditions,” says Navlakha. “By understanding these tradeoffs we may be able to dynamically tune our crop varieties to a changing climate.”

    Professor and Director of Plant Molecular and Cellular Biology Laboratory Joanne Chory, who along with being Howard H. and Maryam R. Newman Chair in Plant Biology is also a Howard Hughes Medical Investigator and one of the paper’s coauthors, adds: “This paper highlights a new principle guiding growth and adaptation of plant architectures, and it raises new questions about the molecular mechanisms driving pattern formation, which we will continue to explore.”

    The work was funded by the Howard Hughes Medical Institute, the Department of Defense/Army Research Laboratory and a Salk Innovation Grant.

    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 6:35 am on July 21, 2017 Permalink | Reply
    Tags: , , , 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
    Office of Communications
    Tel: (858) 453-4100
    press@salk.edu

    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.

    2
    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.

    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 11:57 am on July 4, 2017 Permalink | Reply
    Tags: , , , , , Salk Institute, Tilting the sample gave a more complete dataset   

    From Salk: “Tilted microscopy technique better reveals protein structures” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    July 3, 2017
    No writer credit found

    Cryo-Electron Microscope. No image credit.

    Salk Institute researcher describes new cryo-EM method to facilitate a better understanding of proteins involved in disease.

    The conventional way of placing protein samples under an electron microscope during cryo-EM experiments may fall flat when it comes to getting the best picture of a protein’s structure. In some cases, tilting a sheet of frozen proteins—by anywhere from 10 to 50 degrees—as it lies under the microscope, gives higher quality data and could lead to a better understanding of a variety of diseases, according to new research led by Salk scientist Dmitry Lyumkis.

    2
    Dmitry Lyumkis. Credit: Salk Institute.

    “People have tried to implement tilting before, but there have been a lot of challenges,” says Lyumkis, a Helmsley-Salk Fellow at the Salk Institute and senior author of the new work, published July 3, 2017 in Nature Methods. “We’ve eliminated many of these problems with our new approach.”

    Cryo-EM, or cryo-electron microscopy, is a form of transmission electron microscopy in which samples are quickly cooled to below freezing before being imaged under the microscope. Unlike other methods commonly used to determine the structure of proteins, cryo-EM lets proteins remain in their natural conformations for imaging, which could reveal new information about the structures. Understanding proteins’ structures is a vital step to developing new therapies for disease, such as in the case of HIV.

    Researchers have long assumed that proteins adopt random conformations throughout the frozen grid that’s prepared for cryo-EM experiments, which means that by taking enough images, researchers can put together a full, 3D picture of the protein’s shape(s) from all imaging directions. But for many proteins, the approach seems to fall short, and parts of the proteins’ structures remain missing.

    “Researchers are starting to think that the proteins on a cryo-EM grid don’t adopt random conformations after all, but rather stick to the top or bottom of the sample grid in preferred orientations,” says Lyumkis. “Thus we may not be getting the full picture of proteins’ structures. More importantly, this behavior can prohibit structure determination altogether for select protein samples.”

    To understand the problem, imagine trying to look at the shadows of a dozen tin cans to figure out their shape but seeing only circles because all the cans are exactly upright. By making the light—or electron beam, in the case of cryo-EM—hit the samples at an angle, though, you’d be able to see the true shape better.

    When researchers have tried to tilt samples under a microscope in the past, they’ve been limited by poor resolution: an angle means that the electron beam has to travel through a thicker grid. Samples are also more likely to move within the frozen grid when they’re tilted, blurring out the data. And technically, analyzing data from a tilted sample is also more challenging, since cryo-EM methods were designed with the assumption that the grid containing proteins was always at the same distance from the microscope.

    To tackle these challenges, Lyumkis and his colleagues changed the materials used to create the cryo-EM grid, recorded movies of their data rather than still images, and developed new computational methods to analyze the information.

    When they tested the new approach on the influenza hemagglutinin protein, a notoriously hard protein to characterize using cryo-EM, the team found that tilting the sample gave a more complete dataset. When the protein sample was flat, typical algorithms introduced false positive shape to the protein that wasn’t backed up by experimental data. That wasn’t the case when it was tilted.

    “Due to the geometry of the data collection when we tilt, we fill up much more data characterizing the molecules, giving us a more complete picture of the protein’s shape” says Lyumkis.

    The algorithms that Lyumkis and his team developed—which include ways to analyze whether a cryo-EM experiment is introducing bad data, as well as the methods to interpret a tilted experiment—are now openly available. They hope other researchers will start using them and that it becomes a standard metric for cryo-EM structure validation (since most experimentally derived structures suffer from missing information to different extents).

    “One of the ideas we’re looking at now is whether data collection should always be performed at a tilt rather than in the conventional way,” says Lyumkis. “It won’t hurt and it should help.”

    Other researchers on the study were Yong Zi Tan, Philip Baldwin, Clinton Potter and Bridget Carragher of the New York Structural Biology Center, and Joseph David and James Williamson of The Scripps Research Institute.

    The work and the researchers involved were supported by grants from the Agency for Science, Technology, and Research Singapore, the Leona M. and Harry B. Helmsley Charitable Trust, the U.S. National Institutes of Health, the Jane Coffin Childs Foundation, the National Institute of Aging, the National Institute of General Medical Sciences and the Simons 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 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.

    3
    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.

    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 5:01 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.

    1
    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” 

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    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.

    1
    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.

    1
    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.

    2
    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.

    3
    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.

     
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