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  • richardmitnick 5:59 am on February 13, 2015 Permalink | Reply
    Tags: , Biology, ,   

    From Rock U: “Key to blocking influenza virus may lie in a cell’s own machinery” 

    Rockefeller U bloc

    Rockefeller University

    February 12, 2015
    Zach Veilleux | 212-327-8982
    newswire@rockefeller.edu

    1
    Going viral: To test which virus-fighting proteins could interfere with the spread of an infection, the researchers introduced immune genes individually into cells, before infecting them with Influenza A. Above, all cells’ nuclei appear in blue, infected cells in green.
    Viruses are masters of outsourcing, entrusting their fundamental function – reproduction – to the host cells they infect. But it turns out this highly economical approach also creates vulnerability.

    Researchers at Rockefeller University and their collaborators have found an unexpected way the immune system exploits the flu virus’ dependence on its host’s machinery to create new viruses capable of spreading infection. This discovery suggests a new approach to combating winter’s most unpleasant, and sometimes, deadly curse: the seasonal flu.

    “Influenza A, the virus we studied, relies on a host’s protein-cutting machinery to put the final touches on new viral particles. Our research has shown that the host immune system fights back by turning off this machinery,” says study researcher Charles Rice, Maurice R. and Corinne P. Greenberg Professor in Virology Professor and head of the Laboratory of Virology and Infectious Disease. “This concept, that a host would inhibit its own protein-cutting enzymes in order to fight off a virus, is entirely new.”

    Experiments described today (February 12) in Cell reveal a new function for the well-studied protein known as PAI-1 (plasminogen activator inhibitor 1) as the key to this defensive strategy. PAI-1 shuts down proteases, which are enzymes that break the chemical bonds within protein molecules. PAI-1 is best known for inhibiting proteases involved in the break down of blood clots. After seeing evidence of a new role for PAI-1, the researchers found that human and mouse cells unable to properly produce it appeared more vulnerable to infection by influenza A. In experiments, they used the subtype H1N1, a derivative of the 1918 pandemic flu and a member of a large family of flu viruses that include seasonal flu.

    A cell infected by a virus releases chemical signals known as interferons, which turn up the volume on a legion of defensive genes. “The hundreds of host proteins produced by these interferon-stimulated genes are like an army. We know that, together, they can effectively defend against a viral infection, but we don’t know how the individual soldiers fight back, particularly those that interfere with later stages of viral replication, when the virus exits the cell and spreads the infection,” says first author Meike Dittmann, a postdoc in the lab. Previous work here and elsewhere has explored inhibitors of the early stages of viral replication.

    They started out by testing a large suite of genes activated by interferon. With help from Paul Bieniasz’s Laboratory of Retrovirology at The Rockefeller University and the Aaron Diamond AIDS Research Center, they introduced these individual genes into cells, then infected the cells with the flu. With the knowledge that influenza A’s replication cycle takes about eight hours, they watched to see which genes blocked the ability of influenza to spread. As expected, numerous genes inhibited late stages infection, but one stood out: SERPINE1, the gene that codes for PAI-1.

    Given what was already known about PAI-1, Dittmann suspected how it might help cells fight flu.

    “A virus attacks a cell using fusion proteins, and if these don’t work properly, new virus particles get out of an infected cell just fine, but they cannot spread the infection to other cells. Proteases activate fusion proteins by clipping them, but on its own influenza A doesn’t have the gene for the protease it needs. As a result, the virus relies on the host proteases to do the job,” Dittmann says.

    Subsequent experiments confirmed PAI-1 did indeed prevent the cutting of the fusion protein, known as hemagglutinin, and that high levels of PAI-1 prevented the virus from producing particles capable of spreading the infection. Furthermore, mice that lacked the gene for PAI-1 generally fared worse than their peers when infected with the influenza A virus. Experiments conducted by the team’s collaborators at the MRC National Institute for Medical Research in London used infected tissues cultured from mice’s tracheae to confirm PAI-1’s role in fighting off the infection.

    Human cells were the final step. Researchers in Senior Attending Physician and Professor Jean-Laurent Casanova’s St. Giles Laboratory of Human Genetics combed through a database containing genetic information on patients who had suffered from severe infectious disease to find those with genetic changes that reduced PAI-1. Biopsies taken from these patients had been used to create cell lines, and when cells derived from patients with mutations in SERPINE1 were infected, they accumulated higher loads of the virus than cells derived from people without mutations in the gene.

    “While this study was conducted with Influenza A, our results may have broader implications,” Rice says. “PAI-1 is part of a large family of protease inhibitors, and it’s possible that it, or its close relatives, may interfere with the replication of other viruses that don’t carry genes for their own proteases. This suggests that it may be possible to use a PAI-1-like strategy as a treatment for flu, and possibly other viral infections.”

    See the full article here.

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    Rockefeller U Campus

    The Rockefeller University is a world-renowned center for research and graduate education in the biomedical sciences, chemistry, bioinformatics and physics. The university’s 76 laboratories conduct both clinical and basic research and study a diverse range of biological and biomedical problems with the mission of improving the understanding of life for the benefit of humanity.

    Founded in 1901 by John D. Rockefeller, the Rockefeller Institute for Medical Research was the country’s first institution devoted exclusively to biomedical research. The Rockefeller University Hospital was founded in 1910 as the first hospital devoted exclusively to clinical research. In the 1950s, the institute expanded its mission to include graduate education and began training new generations of scientists to become research leaders around the world. In 1965, it was renamed The Rockefeller University.

     
  • richardmitnick 5:18 am on February 10, 2015 Permalink | Reply
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    From phys.org: “Bionic leaf: Researchers use bacteria to convert solar energy into liquid fuel” 

    physdotorg
    phys.org

    1
    Plant cells with visible chloroplasts (from a moss, Plagiomnium affine) Credit: Wikipedia

    Harvesting sunlight is a trick plants mastered more than a billion years ago, using solar energy to feed themselves from the air and water around them in the process we know as photosynthesis.

    Scientists have also figured out how to harness solar energy, using electricity from photovoltaic cells to yield hydrogen that can be later used in fuel cells. But hydrogen has failed to catch on as a practical fuel for cars or for power generation in a world designed around liquid fuels.

    Now scientists from a team spanning Harvard University’s Faculty of Arts and Sciences, Harvard Medical School and the Wyss Institute for Biologically Inspired Engineering at Harvard University have created a system that uses bacteria to convert solar energy into a liquid fuel. Their work integrates an “artificial leaf,” which uses a catalyst to make sunlight split water into hydrogen and oxygen, with a bacterium engineered to convert carbon dioxide plus hydrogen into the liquid fuel isopropanol.

    The findings are published Feb. 9 in PNAS. The co-first authors are Joseph Torella, a recent PhD graduate from the HMS Department of Systems Biology, and Christopher Gagliardi, a postdoctoral fellow in the Harvard Department of Chemistry and Chemical Biology.

    Pamela Silver, the Elliott T. and Onie H. Adams Professor of Biochemistry and Systems Biology at HMS and an author of the paper, calls the system a bionic leaf, a nod to the artificial leaf invented by the paper’s senior author, Daniel Nocera, the Patterson Rockwood Professor of Energy at Harvard University.

    “This is a proof of concept that you can have a way of harvesting solar energy and storing it in the form of a liquid fuel,” said Silver, who is Core Faculty at the Wyss Institute. “Dan’s formidable discovery of the catalyst really set this off, and we had a mission of wanting to interface some kinds of organisms with the harvesting of solar energy. It was a perfect match.”

    Silver and Nocera began collaborating two years ago, shortly after Nocera came to Harvard from MIT. They shared an interest in “personalized energy,” or the concept of making energy locally, as opposed to the current system, which in the example of oil means production is centralized and then sent to gas stations. Local energy would be attractive in the developing world.

    “It’s not like we’re trying to make some super-convoluted system,” Silver said. “Instead, we are looking for simplicity and ease of use.”

    In a similar vein, Nocera’s artificial leaf depends on catalysts made from materials that are inexpensive and readily accessible.

    “The catalysts I made are extremely well adapted and compatible with the growth conditions you need for living organisms like a bacterium,” Nocera said.

    In their new system, once the artificial leaf produces oxygen and hydrogen, the hydrogen is fed to a bacterium called Ralstonia eutropha. An enzyme takes the hydrogen back to protons and electrons, then combines them with carbon dioxide to replicate—making more cells.

    Next, based on discoveries made earlier by Anthony Sinskey, professor of microbiology and of health sciences and technology at MIT, new pathways in the bacterium are metabolically engineered to make isopropanol.

    “The advantage of interfacing the inorganic catalyst with biology is you have an unprecedented platform for chemical synthesis that you don’t have with inorganic catalysts alone,” said Brendan Colón, a graduate student in systems biology in the Silver lab and a co-author of the paper. “Solar-to-chemical production is the heart of this paper, and so far we’ve been using plants for that, but we are using the unprecedented ability of biology to make lots of compounds.”

    The same principles could be employed to produce drugs such as vitamins in small amounts, Silver said.

    The team’s immediate challenge is to increase the bionic leaf’s ability to translate solar energy to biomass by optimizing the catalyst and the bacteria. Their goal is 5 percent efficiency, compared to nature’s rate of 1 percent efficiency for photosynthesis to turn sunlight into biomass.

    “We’re almost at a 1 percent efficiency rate of converting sunlight into isopropanol,” Nocera said. “There have been 2.6 billion years of evolution, and Pam and I working together a year and a half have already achieved the efficiency of photosynthesis.”

    See the full article here.

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    About Phys.org in 100 Words

    Phys.org™ (formerly Physorg.com) is a leading web-based science, research and technology news service which covers a full range of topics. These include physics, earth science, medicine, nanotechnology, electronics, space, biology, chemistry, computer sciences, engineering, mathematics and other sciences and technologies. Launched in 2004, Phys.org’s readership has grown steadily to include 1.75 million scientists, researchers, and engineers every month. Phys.org publishes approximately 100 quality articles every day, offering some of the most comprehensive coverage of sci-tech developments world-wide. Quancast 2009 includes Phys.org in its list of the Global Top 2,000 Websites. Phys.org community members enjoy access to many personalized features such as social networking, a personal home page set-up, RSS/XML feeds, article comments and ranking, the ability to save favorite articles, a daily newsletter, and other options.

     
  • richardmitnick 7:26 pm on February 9, 2015 Permalink | Reply
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    From Rice: “Nano-antioxidants prove their potential” 

    Rice U bloc

    Rice University

    February 9, 2015
    Mike Williams

    Rice-led study shows how particles quench damaging superoxides

    Injectable nanoparticles that could protect an injured person from further damage due to oxidative stress have proven to be astoundingly effective in tests to study their mechanism.

    Scientists at Rice University, Baylor College of Medicine and the University of Texas Health Science Center at Houston (UTHealth) Medical School designed methods to validate their 2012 discovery that combined polyethylene glycol-hydrophilic carbon clusters — known as PEG-HCCs — could quickly stem the process of overoxidation that can cause damage in the minutes and hours after an injury.

    1
    A polyethylene glycol-hydrophilic carbon cluster developed at Rice University has the potential to quench the overexpression of damaging superoxides through the catalytic turnover of reactive oxygen species that can harm biological functions. Illustration by Errol Samuel

    The tests revealed a single nanoparticle can quickly catalyze the neutralization of thousands of damaging reactive oxygen species molecules that are overexpressed by the body’s cells in response to an injury and turn the molecules into oxygen. These reactive species can damage cells and cause mutations, but PEG-HCCs appear to have an enormous capacity to turn them into less-reactive substances.

    The researchers hope an injection of PEG-HCCs as soon as possible after an injury, such as traumatic brain injury or stroke, can mitigate further brain damage by restoring normal oxygen levels to the brain’s sensitive circulatory system.

    The results were reported today in the Proceedings of the National Academy of Sciences.

    “Effectively, they bring the level of reactive oxygen species back to normal almost instantly,” said Rice chemist James Tour. “This could be a useful tool for emergency responders who need to quickly stabilize an accident or heart attack victim or to treat soldiers in the field of battle.” Tour led the new study with neurologist Thomas Kent of Baylor College of Medicine and biochemist Ah-Lim Tsai of UTHealth.

    PEG-HCCs are about 3 nanometers wide and 30 to 40 nanometers long and contain from 2,000 to 5,000 carbon atoms. In tests, an individual PEG-HCC nanoparticle can catalyze the conversion of 20,000 to a million reactive oxygen species molecules per second into molecular oxygen, which damaged tissues need, and hydrogen peroxide while quenching reactive intermediates.

    Tour and Kent led the earlier research that determined an infusion of nontoxic PEG-HCCs may quickly stabilize blood flow in the brain and protect against reactive oxygen species molecules overexpressed by cells during a medical trauma, especially when accompanied by massive blood loss.

    Their research targeted traumatic brain injuries, after which cells release an excessive amount of the reactive oxygen species known as a superoxide into the blood. These toxic free radicals are molecules with one unpaired electron that the immune system uses to kill invading microorganisms. In small concentrations, they contribute to a cell’s normal energy regulation. Generally, they are kept in check by superoxide dismutase, an enzyme that neutralizes superoxides.

    But even mild traumas can release enough superoxides to overwhelm the brain’s natural defenses. In turn, superoxides can form such other reactive oxygen species as peroxynitrite that cause further damage.

    “The current research shows PEG-HCCs work catalytically, extremely rapidly and with an enormous capacity to neutralize thousands upon thousands of the deleterious molecules, particularly superoxide and hydroxyl radicals that destroy normal tissue when left unregulated,” Tour said.

    “This will be important not only in traumatic brain injury and stroke treatment, but for many acute injuries of any organ or tissue and in medical procedures such as organ transplantation,” he said. “Anytime tissue is stressed and thereby oxygen-starved, superoxide can form to further attack the surrounding good tissue.”

    The researchers used an electron paramagnetic resonance spectroscopy technique that gets direct structure and rate information for superoxide radicals by counting unpaired electrons in the presence or absence of PEG-HCC antioxidants. Another test with an oxygen-sensing electrode, peroxidase and a red dye confirmed the particles’ ability to catalyze superoxide conversion.

    “In sharp contrast to the well-known superoxide dismutase, PEG-HCC is not a protein and does not have metal to serve the catalytic role,” Tsai said. “The efficient catalytic turnover could be due to its more ‘planar,’ highly conjugated carbon core.”

    The tests showed the number of superoxides consumed far surpassed the number of possible PEG-HCC bonding sites. The researchers found the particles have no effect on important nitric oxides that keep blood vessels dilated and aid neurotransmission and cell protection, nor was the efficiency sensitive to pH changes.

    “PEG-HCCs have enormous capacity to convert superoxide to oxygen and the ability to quench reactive intermediates while not affecting nitric oxide molecules that are beneficial in normal amounts,” Kent said. “So they hold a unique place in our potential armamentarium against a range of diseases that involve loss of oxygen and damaging levels of free radicals.”

    The study also determined PEG-HCCs remain stable, as batches up to 3 months old performed as good as new.

    Graduate student Errol Samuel and alumna Daniela Marcano, both of Rice, and Vladimir Berka, a senior research scientist at UTHealth, are lead authors of the study. Co-authors are Rice alumnus Austin Potter; alumnus Brittany Bitner and associate professor Robia Pautler of Baylor College of Medicine; instructor Gang Wu of UTHealth and Roderic Fabian of Baylor College of Medicine and the Michael E. DeBakey Veterans Affairs Medical Center.

    Kent is a professor of neurology and director of stroke research and education at Baylor College of Medicine and chief of neurology and a member of the Center for Translational Research on Inflammatory Diseases at the DeBakey Center. Tour is the T.T. and W.F. Chao Chair in Chemistry as well as a professor of materials science and nanoengineering and of computer science and a member of Rice’s Richard E. Smalley Institute for Nanoscale Science and Technology. Tsai is a professor of hematology at UTHealth and adjunct professor of biochemistry and cell biology at Rice.

    The Mission Connect Mild Traumatic Brain Injury Consortium from the Department of Defense and the National Institutes of Health, the Alliance for NanoHealth and UTHealth supported the research.

    See the full article here.

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    Rice U campus

    In his 1912 inaugural address, Rice University president Edgar Odell Lovett set forth an ambitious vision for a great research university in Houston, Texas; one dedicated to excellence across the range of human endeavor. With this bold beginning in mind, and with Rice’s centennial approaching, it is time to ask again what we aspire to in a dynamic and shrinking world in which education and the production of knowledge will play an even greater role. What shall our vision be for Rice as we prepare for its second century, and how ought we to advance over the next decade?

    This was the fundamental question posed in the Call to Conversation, a document released to the Rice community in summer 2005. The Call to Conversation asked us to reexamine many aspects of our enterprise, from our fundamental mission and aspirations to the manner in which we define and achieve excellence. It identified the pressures of a constantly changing and increasingly competitive landscape; it asked us to assess honestly Rice’s comparative strengths and weaknesses; and it called on us to define strategic priorities for the future, an effort that will be a focus of the next phase of this process.

     
  • richardmitnick 5:18 am on February 4, 2015 Permalink | Reply
    Tags: , Biology, ,   

    From SLAC: “Record Keeping Helps Bacteria’s Immune System Fight Invaders” 


    SLAC Lab

    February 3, 2015

    Bacteria have a sophisticated means of defending themselves, and they need it: more viruses infect bacteria than any other biological entity.

    Two experiments undertaken at the Department of Energy’s SLAC National Accelerator Laboratory provide new insight at the heart of bacterial adaptive defenses in a system called CRISPR, short for Clustered Regularly Interspaced Short Palindromic Repeat.

    This portion of bacteria’s immune system works as a record keeper, taking note of attacking viruses’ identities and storing that information by integrating fragments of the virus’ DNA into its own DNA. In this way, CRISPRs maintain genetic records of previously encountered viruses, making it easier for the bacteria’s immune system to send out complexes that destroy viral invaders by identifying and cutting up the recognized DNA sequences.

    The studies published last year in Science not only reveal important information about how bacteria repel attacking viruses, but also could potentially improve the prevention of disease in humans. Researchers are currently studying ways of preventing and treating cystic fibrosis, blood disorders and HIV by harnessing the CRISPR system to replace one version of a gene with another or to add a working copy for a mutated gene.

    Scientists studied one particular CRISPR-associated complex called Cascade using bright X-rays at SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL)., a DOE Office of Science User Facility. In the bacteria Escherichia coli, 11 proteins assemble together with an RNA guide that helps Cascade target invading DNA sequences. Once Cascade confirms that the target DNA is from an invader, a molecular signal recruits a nuclease called Cas3 to finish off the invader by chewing it up.

    1`
    An overview of the crystal structure of Cascade, showing each gene in a different color. The red ribbon represents the RNA guide. (Ryan N. Jackson et al.)

    SLAC SSRL TunnelSLAC SSRL

    Previous work by Blake Wiedenheft, the Montana State University assistant professor of microbiology and immunology who led one of the studies, and his colleagues revealed Cascade’s seahorse-shaped architecture, but studies undertaken at SSRL now reveal how all the parts of this machine assemble into a functional surveillance machine that patrols the intracellular environment for invading DNA.

    2
    A simplified representation of the Cascade RNA guide (green) forming an under-wound ribbon-like structure with invading viral DNA (orange). (Scott Bailey et al.)

    “Determining high-resolution structures of large macromolecules remains challenging,” Wiedenheft said. “Several technical aspects of SSRL, including intensity of light, ability to focus the beam, and shutterless X-ray detector made these results possible.”

    The studies also revealed that Cascade’s RNA guide does not twist together with the viral DNA to form a helix, as was expected. Instead, they form an under-wound ribbon-like structure.

    “A high-resolution structure is essentially a molecular blueprint of a biological machine,” said Wiedenheft. Determining the structure of this complex “is a technical accomplishment that provides the first molecular explanation of how all the parts assemble into a functional surveillance machine.”

    See the full article here.

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    SLAC Campus
    SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the DOE’s Office of Science.
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  • richardmitnick 2:27 pm on January 30, 2015 Permalink | Reply
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    From Harvard: “DNA nanoswitches reveal how life’s molecules connect” 

    Harvard University

    Harvard University

    1

    Jan 29, 2015
    Wyss Institute for Biologically Inspired Engineering at Harvard University
    Kat J. McAlpine, katherine.mcalpine@wyss.harvard.edu, +1 617-432-8266

    Harvard Medical School
    David Cameron, david_cameron@hms.harvard.edu, +1 617-432-0441

    Boston Children’s Hospital
    Keri Stedman, keri.stedman@childrens.harvard.edu, +1 617-919-3110

    An accessible new way to study molecular interactions could lower cost and time associated with discovering new drugs

    A complex interplay of molecular components governs almost all aspects of biological sciences — healthy organism development, disease progression, and drug efficacy are all dependent on the way life’s molecules interact in the body. Understanding these bio–molecular interactions is critical for the discovery of new, more effective therapeutics and diagnostics to treat cancer and other diseases, but currently requires scientists to have access to expensive and elaborate laboratory equipment.

    Now, a new approach developed by researchers at the Wyss Institute for Biologically Inspired Engineering, Boston Children’s Hospital and Harvard Medical School promises a much faster and more affordable way to examine bio–molecular behavior, opening the door for scientists in virtually any laboratory world–wide to join the quest for creating better drugs. The findings are published in February’s issue of Nature Methods.

    “Bio–molecular interaction analysis, a cornerstone of biomedical research, is traditionally accomplished using equipment that can cost hundreds of thousands of dollars,” said Wyss Associate Faculty member Wesley P. Wong, Ph.D., senior author of study. “Rather than develop a new instrument, we’ve created a nanoscale tool made from strands of DNA that can detect and report how molecules behave, enabling biological measurements to be made by almost anyone, using only common and inexpensive laboratory reagents.”

    Wong, who is also Assistant Professor at Harvard Medical School in the Departments of Biological Chemistry & Molecular Pharmacology and Pediatrics and Investigator at the Program in Cellular and Molecular Medicine at Boston Children’s Hospital, calls the new tools DNA “nanoswitches”.

    Nanoswitches comprise strands of DNA onto which molecules of interest can be strategically attached at various locations along the strand. Interactions between these molecules, such as successful binding of a drug compound with its intended target, such as a protein receptor on a cancer cell, cause the shape of the DNA strand to change from an open and linear shape to a closed loop. Wong and his team can easily separate and measure the ratio of open DNA nanoswitches vs. their closed counterparts through gel electrophoresis, a simple lab procedure already in use in most laboratories, that uses electrical currents to push DNA strands through small pores in a gel, sorting them based on their shape.

    “Our DNA nanoswitches dramatically lower barriers to making traditionally complex measurements,” said co–first author Ken Halvorsen, formerly of the Wyss Institute and currently a scientist at the RNA Institute at University of Albany. “All of these supplies are commonly available and the experiments can be performed for pennies per sample, which is a staggering comparison to the cost of conventional equipment used to test bio–molecular interactions.”

    To encourage adoption of this method, Wong and his team are offering free materials to colleagues who would like to try using their DNA nanoswitches.

    “We’ve not only created starter kits but have outlined a step–by–step protocol to allow others to immediately implement this method for research in their own labs, or classrooms,” said co–first author Mounir Koussa, a Ph.D. candidate in neurobiology at Harvard Medical School.

    “Wesley and his team are committed to making an impact on the way bio–molecular research is done at a fundamental level, as is evidenced by their efforts to make this technology accessible to labs everywhere,” said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Boston Children’s Hospital and Harvard Medical School and a Professor of Bioengineering at Harvard SEAS. “Biomedical researchers all over the world can start using this new method right away to investigate how biological compounds interact with their targets, using commonly–available supplies at very low cost.”

    See the full article here.

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

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  • richardmitnick 7:18 am on January 30, 2015 Permalink | Reply
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    From MIT Tech Review: “U.S. To Develop DNA Study of One Million People” 

    MIT Technology Review
    M.I.T Technology Review

    January 30, 2015
    Antonio Regalado

    U.S. President Barack Obama is proposing to spend $215 million on a “precision medicine” initiative the centerpiece of which will be a national study involving the health records and DNA of one million volunteers, administration officials said yesterday.

    Precision medicine refers to treatments tailored to a person’s genetic profile, an idea already transforming how doctors fight cancer as well as some rare diseases.

    The Obama plan, including support for studies of cancer and rare disease, is part of a shift away from “one-size-fits-all” medicine, Jo Handelsman, associate director for the White House Office of Science and Technology Policy, said in a briefing yesterday. She called precision medicine “a game changer that holds the potential to revolutionize how we approach health in this country and around the world.”

    The White House said the largest part of the money, $130 million, would go to the National Institutes of Health in order to create a population-scale study of how peoples’ genes, environment, and lifestyle affect their health.

    According to Francis Collins, director of the National Institutes of Health, the study would reach a million people by merging data from several large studies already underway, as well as by recruiting new volunteers. Details of the study still need to be sorted out, said Collins, but it could eventually involve completely decoding the genomes of hundreds of thousands of people.

    Officials indicated that patients might have more access to data generated about them than is usually the case in research studies. That is partly because scientists will need the ability to re-contact them, should their genes prove interesting.

    “We aren’t just talking about research but also about patients’ access to their own data, so they can participate fully in decisions about their health that affect them,” said John Holdren, director of the White House Office of Science and Technology Policy.

    Collins said the U.S. is not seeking to create a single bio-bank. Instead, it would be look to combine data from among what he called more than 200 large American health studies involving at least two million people. “Fortunately we don’t have to start from scratch,” said Collins. “The challenge of this initiative is to link those together. It’s more a distributed approach than centralized.”

    Collins warned that “interoperability” of medical record systems and gene databases could be the most significant obstacle to the NIH’s plans.

    A lack of standards is one reason why the U.S. lags some European countries, which already have large, well-organized studies linking genomics to national health records. There is competition from the private sector as well, where precision medicine is a hot subject drawing large investments.

    For instance, one of the world’s largest private bio-banks, of 800,000 spit samples, is owned by a startup, 23andMe, in Silicon Valley with its eyes on being a kind of Facebook of gene research.

    The entrepreneur J. Craig Venter, a one-time rival of the NIH in sequencing the first human genome, announced plans a year ago to sequence one million genomes by 2020 using private funding.

    In recent weeks, NIH officials met with administrators from the Veteran’s Health Administration, whose ongoing “Million Veterans Project” has already collected DNA samples from 343,000 former soldiers, and partially analyzed the DNA of 200,000 participants.

    “There is a lot of effort to avoid duplication since no one has enough money, and I would expect these programs to work together,” said Timothy O’Leary, chief research and development officer for the V.A., which is already spending $30 million a year on its study. However, he added that before sharing data the VA would need guarantees that veterans’ private information was not at risk.

    If Obama’s budget is approved, the NIH will hand out the money to academic centers. However, much of the cash will trickle down to tech companies hired to store and organize the data, as well as to makers of gene sequencing instruments. Illumina of San Diego, which sells the most popular models of DNA sequencing machines, is likely to be the single largest financial beneficiary of Obama’s plan in the short term.

    David Goldstein, director of a new institute for genome medicine at Columbia University, called the Obama plan part of an irreversible drive towards obtaining more and more complete genetic information on people as part of routine medicine. “The writing is one the wall. We are all going to be sequenced, the question is just who does it and what is done with it,” said Goldstein. “The challenge will be to do good things with the data.”

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    The mission of MIT Technology Review is to equip its audiences with the intelligence to understand a world shaped by technology.

     
  • richardmitnick 3:42 pm on January 29, 2015 Permalink | Reply
    Tags: , Bill and Melinda Gates Foundation, Biology, , ,   

    From Stanford: “Stanford launches major effort to expedite vaccine discovery with $50 million grant” 

    Stanford University Name
    Stanford University

    January 29, 2015
    Anneke Cole, Office of Development, Stanford University: (650) 724-3298, annekec@stanford.edu

    Stanford University today announced that it has received a grant from the Bill & Melinda Gates Foundation to accelerate efforts in vaccine development. The $50 million grant over 10 years will build on existing technology developed at Stanford and housed in the Human Immune Monitoring Core, and will establish the Stanford Human Systems Immunology Center. The center aims to better understand how the immune system can be harnessed to develop vaccines for the world’s most deadly infectious diseases.

    While illnesses like polio and measles are now readily preventable, scientists have been stymied in their efforts to fight diseases such as HIV and malaria. In part, this is because large-scale clinical trials can cost hundreds of millions of dollars and can take up to 10 years to determine the success – or often failure – of a vaccine candidate.

    The work funded through the new center will enable researchers in diverse fields of study at Stanford and other institutions to use advanced immunological tools to understand how vaccines protect and to help prioritize the most promising vaccines for clinical trials. The center will be led by Mark Davis of Stanford’s School of Medicine and will also involve faculty in the School of Engineering. Their effort furthers the university’s commitment to addressing global problems through novel, interdisciplinary collaborations.

    1
    Professor Mark Davis of the Stanford School of Medicine will lead the new Stanford Human Systems Immunology Center, established with a grant from the Bill & Melinda Gates Foundation to aid vaccine research.

    “Effective vaccines are urgently needed to prevent disease and save lives,” said John L. Hennessy, president of Stanford University. “This grant will allow Stanford to leverage advances in technology and accelerate progress in this important area.”

    The Stanford Human Systems Immunology Center will draw upon a repertoire of technologies, many of which have been pioneered at Stanford, to provide a detailed profile of the human immune response. Seed grants will be made available to Stanford faculty, as well as investigators from other institutions, in order to fuel innovations in immunology and vaccine-related efforts.

    Davis, the center’s principal investigator, said animal models of vaccines have not been successful in most cases, as multiple vaccine candidates shown to work in mice and non-human primates have failed in human trials.

    “What we need is a new generation of vaccines and new approaches to vaccination,” said Davis, who is the Burt and Marion Avery Family Professor of Immunology and director of the Stanford Institute for Immunity, Transplantation, and Infection. “This will require a better understanding of the human immune response and clearer predictions about vaccine efficacy for particular diseases.”

    Davis will be joined in the effort by Holden Maecker, associate professor in the Department of Microbiology and Immunology and director of the Human Immune Monitoring Center; Garry Nolan, the Rachford and Carlota A. Harris Professor, also in the Department of Microbiology and Immunology; Atul Butte, associate professor of pediatrics and genetics and, by courtesy, computer science; Yvonne Maldonado, professor of pediatrics and of health policy and research; Karla Kirkegaard, the Violetta L. Horton Research Professor and professor of genetics; Peter Kim, the Virginia and D. K. Ludwig Professor in Biochemistry; Thomas Baer, executive director of the Stanford Photonics Research Center; and other faculty.

    The researchers also plan to analyze why some people are able to effectively fight off pathogens, while others remain vulnerable. For instance, many millions of people are carriers of the tuberculosis bacteria, yet fewer than 10 percent develop active disease.

    “This grant will provide crucial support to Stanford’s world-class scientists as they collaborate with investigators around the globe to assess vaccines against some of the most formidable diseases of our time,” said Lloyd Minor, dean of the School of Medicine. “The Stanford Human Systems Immunology Center will help the most promising vaccine candidates to move quickly and efficiently from the lab to the front lines of treatment, impacting countless lives.”

    “We are pleased to make this grant, which is all about enabling collaboration,” said Chris Wilson, director of the Discovery and Translational Sciences program at the Bill & Melinda Gates Foundation. “It will enable vaccinologists to take advantage of the state-of-the-art technologies that Stanford has developed to monitor the human immune response and allow Stanford investigators to collaborate to help solve the real-world problems we face when trying to harness the power of the immune system to provide protection for those in the developing world.”

    Stanford has a long track record in immunology. In 1970, the late Professor Len Herzenberg invented the fluorescence-activated cell sorter (FACS), a revolutionary technique that is now a mainstay in labs around the world. In the last decade, Stanford scientists have developed or refined a host of other sophisticated tools that are transforming the ability to understand immune responses in humans at a deep level. These include technologies that can rapidly analyze individual cells and tools that can provide a detailed portrait of the human immune system, with all of its many components.

    “We hope our work will have a profound effect on our ability to combat diseases of the developing world,” said Davis, who is also an investigator at the Howard Hughes Medical Institute.

    See the full article here.

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  • richardmitnick 10:40 am on January 27, 2015 Permalink | Reply
    Tags: , Biology,   

    From MIT: “Biology, driven by data” 


    MIT News

    January 27, 2015
    Anne Trafton | MIT News Office

    1
    Ernest Fraenkel (No image credit)

    Cells are incredibly complicated machines with thousands of interacting parts — and disruptions to any of those interactions can cause disease.

    Tracing those connections to seek the root cause of disease is a daunting task, but it is one that MIT biological engineer Ernest Fraenkel relishes. His lab takes a systematic approach to the problem: By comparing datasets that include thousands of events inside healthy and diseased cells, they can try to figure out what has gone awry in cells that are not functioning properly.

    “The central challenge of this field is how you take all those different kinds of data to get a coherent picture of what’s going on in a cell, what is wrong in a diseased cell, and how you might fix it,” says Fraenkel, an associate professor of biological engineering.

    This type of computational modeling of biological interactions, known as systems biology, can help to reveal possible new drug targets that might not emerge through more traditional biological studies. Using this approach, Fraenkel has deciphered some key interactions that underlie Huntington’s disease as well as glioblastoma, an incurable type of brain cancer.

    Science without borders

    As a high-school student in New York City, Fraenkel had broad interests, and participated in a special program where physics, chemistry, and biology were taught together. The program’s teacher, a Columbia University student, suggested that Fraenkel do some summer research at a lab at Columbia. The lab was run by Cyrus Levinthal, a physicist who had previously taught one of the first biophysics classes at MIT.

    “He had this cool lab where they were doing image analysis of neurons, and modeling proteins, and doing experiments. I just thought it was fantastic. That’s when I decided I wanted to go into science,” Fraenkel recalls.

    He enjoyed the lab so much that he dropped out of high school and starting working there full time, while also taking a few classes at Columbia. After earning a high-school equivalency degree, Fraenkel went to Harvard University to study chemistry and physics, then earned his PhD in biology from MIT. As in high school, he was drawn to all of the sciences, and enjoyed pursuing knowledge from all angles, ignoring the traditional boundaries between fields.

    “My early experience was that they were all deeply connected,” Fraenkel says.

    As a graduate student, he studied structural biology, which uses tools such as X-ray crystallography to understand biological molecules. “What drew me to the field was really the fact that it was very data-rich in a way that biology, at the time, was not,” Fraenkel says.

    However, that was about to change: While Fraenkel was doing a postdoctoral fellowship in structural biology at Harvard, new techniques — such as genome sequencing and measurement of RNA levels inside cells — were generating huge amounts of information. Helping to crunch those numbers seemed an enticing prospect.

    “As I was finishing up my postdoc I was realizing more and more that I wanted to study biology at a more general level,” Fraenkel says. “I really wanted to find out whether there was a more systematic way of trying to understand biology.”

    After leaving Harvard, he became a Whitehead Fellow, allowing him to set up his own lab at the Whitehead Institute and pursue his new interest in systems biology. From there, he joined MIT’s Department of Biological Engineering, which had just been formed.

    Network analysis

    Now, Fraenkel’s lab analyzes vast amounts of data, including not only genomic data but also measurements of proteins and other molecules found in cells. For each set of cells, healthy or diseased, he tries to devise models that could explain what is producing the data. “One way to think about it is a map of a city where these proteins or genes are lighting up different things, and you have to figure out what the wiring is underneath that’s got them talking to each other,” he says.

    To do that, his team uses algorithms they have developed themselves or adapted from network analysis strategies used to analyze the Internet. In the biological networks that Fraenkel studies, connections form between nodes representing a protein, gene, or other small molecule. Nodes that differ between diseased and healthy cells light up in a different color. Ideally, just a few such nodes would light up, but this is usually not the case, Fraenkel says. Instead, you end up with a wiring diagram with color all over the place.

    “We lovingly call those things ‘hairballs,’” he says. “You get these giant hairball diagrams which really haven’t made the problem any easier — in fact, they’ve made it harder. So our algorithms go into that hairball and try to figure out which piece of it is most relevant to the disease, by weighing the probability of different kinds of events being disease-relevant.”

    Those algorithms filter out the irrelevant information, or noise, and zoom in on the pieces of the network that seem to be the most likely to be related to the disease in question. Then, the researchers do experiments in living cells or animals to test the models generated by the algorithms.

    Using this approach, Fraenkel has developed model networks for Huntington’s disease and glioblastoma. Such studies have revealed interactions that might never have been otherwise identified: For example, blocking estrogen can help prevent the growth of glioblastoma cells.

    “The fundamental thing we’re trying to do is take an unbiased view of the biology,” Fraenkel says. “We’re going to look everywhere. We’ll let the data tell us which processes are important and which ones are not.”

    See the full article here.

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  • richardmitnick 8:23 am on January 27, 2015 Permalink | Reply
    Tags: , Biology, ,   

    From Stanford: “Stanford bioengineers develop tool for reprogramming genetic code” 

    Stanford University Name
    Stanford University

    January 26, 2015
    Bjorn Carey

    Biology relies upon the precise activation of specific genes to work properly. If that sequence gets out of whack, or one gene turns on only partially, the outcome can often lead to a disease.

    Now, bioengineers at Stanford and other universities have developed a sort of programmable genetic code that allows them to preferentially activate or deactivate genes in living cells. The work is published in the current issue of Cell, and could help usher in a new generation of gene therapies.

    1
    Stanford bioengineers have developed a new tool that allows them to preferentially activate or deactivate genes in living cells.

    The technique is an adaptation of CRISPR, itself a relatively new genetic tool that makes use of a natural defense mechanism that bacteria evolved over millions of years to slice up infectious virus DNA.

    2
    Diagram of the possible mechanism for CRISPR.

    CRISPRs (clustered regularly interspaced short palindromic repeats) are DNA loci containing short repetitions of base sequences. Each repetition is followed by short segments of “spacer DNA” from previous exposures to a virus.[2]

    Standard CRISPR consists of two components: a short RNA that matches a particular spot in the genome, and a protein called Cas9 that snips the DNA in that location. For the purposes of gene editing, scientists can control where the protein snips the genome, insert a new gene into the cut and patch it back together.

    Inserting new genetic code, however, is just one way to influence how the genome is expressed. Another involves telling the cell how much or how little to activate a particular gene, thus controlling how much protein a cell produces from that gene and altering its behavior.

    It’s this action that Lei Stanley Qi, an assistant professor of bioengineering and of chemical and systems biology at Stanford, and his colleagues aim to manipulate.

    Influencing the genome

    In the new work, the researchers describe how they have designed the CRISPR molecule to include a second piece of information on the RNA, instructing the molecule to either increase (upregulate) or decrease (downregulate) a target gene’s activity, or turn it on/off entirely.

    Additionally, they designed it so that it could affect two different genes at once. In a cell, the order or degree in which multiple genes are activated can produce different metabolic products.

    “It’s like driving a car. You control the wheel to control direction, and the engine to control the speed, and how you balance the two determines how the car moves,” Qi said. “We can do the same thing in the cell by up- or downregulating genes, and produce different outcomes.”

    As a proof of principle, the scientists used the technique to take control of a yeast metabolic pathway, turning genes on and off in various orders to produce four different end products. They then tested it on two mammalian genes that are important in cell mobility, and were able to control the cell’s direction and how fast it moved.

    Future therapies

    The ability to control genes is an attractive approach in designing genetic therapies for complex diseases that involve multiple genes, Qi said, and the new system may overcome several of the challenges of existing experimental therapies.

    “Our technique allows us to directly control multiple specific genes and pathways in the genome without expressing new transgenes or uncontrolled behaviors, such as producing too much of a protein, or doing so in the wrong cells,” Qi said. “We could eventually synthesize tens of thousands of RNA molecules to control the genome over a whole organism.”

    Next, Qi plans to test the technique in mice and refine the delivery method. Currently the scientists use a virus to insert the molecule into a cell, but he would eventually like to simply inject the molecules into an organism’s blood.

    “That is what is so exciting about working at Stanford, because the School of Medicine’s immunology group is just around the corner, and working with them will help us address how to do this without triggering an immune response,” said Qi, who is a member of the interdisciplinary Stanford ChEM-H institute. “I’m optimistic because everything about this system comes naturally from cells, and should be compatible with any organism.”

    See the full article here.

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    Leland and Jane Stanford founded the University to “promote the public welfare by exercising an influence on behalf of humanity and civilization.” Stanford opened its doors in 1891, and more than a century later, it remains dedicated to finding solutions to the great challenges of the day and to preparing our students for leadership in today’s complex world. Stanford, is an American private research university located in Stanford, California on an 8,180-acre (3,310 ha) campus near Palo Alto. Since 1952, more than 54 Stanford faculty, staff, and alumni have won the Nobel Prize, including 19 current faculty members

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  • richardmitnick 8:02 am on January 27, 2015 Permalink | Reply
    Tags: , , Biology,   

    From AAAS: “How Earth’s earliest life overcame a genetic paradox” 

    AAAS

    AAAS

    26 January 2015
    Tim Wogan

    1
    The unique temperature conditions of hydrothermal vents like this one could have favored the evolution of complex life.

    On ancient Earth, the earliest life encountered a paradox. Chains of RNA—the ancestor of DNA—were floating around, haphazardly duplicating themselves. Scientists know that eventually, these RNA chains must have become longer and longer, setting the stage for the evolution of complex life forms like amoebas, worms, and eventually humans. But under all current models, shorter RNA molecules, having less material to copy, would have reproduced faster, favoring the evolution of primitive organisms over complex ones. Now, new research offers a potential solution: Longer RNA chains could have hidden out in porous rocks near volcanic sites such as hydrothermal ocean vents, where unique temperature conditions might have helped complex organisms evolve.

    Hydrothermal vents are fissures in Earth’s crust that pump out superheated water. They would have been common on early Earth, which was more tectonically active than the planet is today, says Dieter Braun, an experimental biophysicist at Ludwig Maximilian University in Munich, Germany. The water in hydrothermal vents is particularly rich in nutrients, making them promising sites for the origin of life.

    To figure out if hydrothermal vents could have given the evolution of complex life a boost, Braun and his colleagues examined the physics of a theoretical single pore in the rock surrounding a vent. The pore is open at the top and at the bottom and filled with a dilute solution of RNA molecules of various lengths. The solution on the hot side—the one closer to the stream of superheated water—would become less dense and rise up through the pore. Some of it would escape at the top, to be replenished by more nutrient-rich fluid entering at the bottom. The remainder would diffuse across to the cold side of the pore and drop back down. A complex physical effect called thermophoresis causes charged molecules in a solution to accumulate in colder water, and the longer chains, having more charge, would do this more often than shorter chains. Therefore, the shorter RNA chains would be more likely to escape out of the top of the pore, whereas the longer ones would stay trapped inside where, continually fed by nutrients, they could reproduce. Better still, Braun says, the continuous temperature cycling could actually help split the RNA double helix apart, making it easier for it to reproduce.

    To test this elaborate hypothesis, Braun and his colleagues constructed a simulated piece of porous rock from a network of tiny glass capillary tubes heated on one side. They allowed dissolved fragments of DNA to be washed into the tubes from the bottom. Ideally, they would have used RNA, but Braun explains that there’s no good way to reproduce RNA in a lab, whereas it’s easy to reproduce DNA with a standard laboratory process called PCR. “All the thermophoresis and the characteristics of the trapping mechanism are the same for DNA and RNA,” he says. Once they let the experiment run, the researchers found that longer chains of DNA were more likely to accumulate inside the tubes than shorter chains were. As a result, the longer strands reproduced much better inside the pores and their populations grew, whereas the shorter strands were diluted so much that they went extinct, the team reports online today in Nature Chemistry.

    It’s “nice chemistry,” says marine chemist Jeffrey Bada of the University of California (UC), San Diego, but he is not convinced that hydrothermal vents, or any other likely habitat on early Earth, could have provided the conditions created in the lab: “The processes outlined are not likely to take place on a significant scale on the Earth or elsewhere.” Biochemist Irene Chen of UC Santa Barbara disagrees and even thinks the research opens a door to studying environments beyond just volcanic ones. She suggests rock pores hotter on one side than the other could result from solar, as well as hydrothermal, heating, expanding the types of environments that could have favored the evolution of complex life. A physical environment that could plausibly have existed on the early Earth “actually selects for longer RNA sequences,” she says. “The extra length is basically room for biological creativity.”

    See the full article here.

    The American Association for the Advancement of Science is an international non-profit organization dedicated to advancing science for the benefit of all people.

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