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  • richardmitnick 4:40 pm on November 21, 2014 Permalink | Reply
    Tags: , Biology, , , ,   

    From SLAC: “Robotics Meet X-ray Lasers in Cutting-edge Biology Studies” 


    SLAC Lab

    November 21, 2014

    Platform Brings Speed, Precision in Determining 3-D Structure of Challenging Biological Molecules

    Scientists at the Department of Energy’s SLAC National Accelerator Laboratory are combining the speed and precision of robots with one of the brightest X-ray lasers on the planet for pioneering studies of proteins important to biology and drug discovery.

    The new system uses robotics and other automated components to precisely maneuver delicate samples for study with the X-ray laser pulses at SLAC’s Linac Coherent Light Source (LCLS). This will speed efforts to map the 3-D structures of nanoscale crystallized proteins, which are important for designing targeted drugs and synthesizing natural systems and processes.

    s
    This illustration shows an experimental setup used in crystallography experiments at SLAC’s Linac Coherent Light Source X-ray laser. The drum-shaped container at left stores supercooled crystal samples that are fetched by a robotic arm and delivered to another device, called a goniometer. The goniometer moves individual crystals through the X-ray beam, which travels from the pipe at upper left toward the lower right. A detector, right, captures X-ray diffraction patterns produced as the X-rays pass through the crystal samples. (SLAC National Accelerator Laboratory)

    i
    Equipment used in a highly automated X-ray crystallography system at SLAC’s Linac Coherent Light Source X-ray laser. The metal drum at lower left contains liquid nitrogen for cooling crystallized samples studied with LCLS’s intense X-ray pulses. (SLAC National Accelerator Laboratory)

    SLAC LCLS
    SLAC LCLS

    A New Way to Study Biology

    “This is an efficient, highly reliable and automated way to obtain high-resolution 3-D structural information from small sizes and volumes of samples, and from samples that are too delicate to study using other X-ray sources and techniques,” said Aina Cohen, who oversaw the development of the platform in collaboration with staff at LCLS and at SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL), both DOE Office of Science User Facilities.

    SLAC SSRL
    SLAC SSRL

    She is co-leader of the Macromolecular Crystallography group in the Structural Molecular Biology (SMB) program at SSRL, which has used robotic sample-handling systems to run remote-controlled experiments for a decade.

    The new setup at LCLS is described in the Oct. 31 edition of Proceedings of the National Academy of Sciences. It includes a modified version of a “goniometer,” a sample-handling device in use at SSRL and many other synchrotrons, as well as a custom version of an SSRL-designed software package that pinpoints the position of crystals in arrays of samples.

    LCLS, with X-ray pulses a billion times brighter than more conventional sources, has already allowed scientists to explore biological samples too small or fragile to study in detail with other tools. The new system provides added flexibility in the type of samples and sample-holders that can be used in experiments.

    Rather than injecting millions of tiny, randomly tumbling crystallized samples into the path of the pulses in a thin liquid stream – common in biology experiments at LCLS – the goniometer-based system places crystals one at a time into the X-ray pulses. This greatly reduces the number of crystals needed for structural studies on rare and important samples that require a more controlled approach.

    Early Successes

    “This system adapts common synchrotron techniques for use at LCLS, which is very important,” said Henrik Lemke, staff scientist at LCLS. “There is a large community of scientists who are familiar with the goniometer technique.”

    The system has already been used to provide a complete picture of a protein’s structure in about 30 minutes using only five crystallized samples of an enzyme, moved one at a time into the X-rays for a sequence of atomic-scale “snapshots.”

    It has also helped to determine the atomic-scale structures of an oxygen-binding protein found in muscles, and another protein that regulates heart and other muscle and organ functions.

    “We have shown that this system works, and we can further automate it,” Cohen said. “Our goal is to make it easy for everyone to use.”

    Many biological experiments at LCLS are conducted in air-tight chambers. The new setup is designed to work in the open air and can also be used to study room-temperature samples, although most of the samples used in the system so far have been deeply chilled to preserve their structure. One goal is to speed up the system so it delivers samples and measures the resulting diffraction patterns as fast as possible, ideally as fast as LCLS delivers pulses: 120 times a second.

    The goniometer setup is the latest addition to a large toolkit of systems that deliver a variety of samples to the LCLS beam, and a new experimental station called MFX that is planned at LCLS will incorporate a permanent version.

    Team Effort

    Developed through a collaboration of SSRL’s Structural Molecular Biology program and the Stanford University School of Medicine, the LCLS goniometer system reflects increasing cooperation in the science of SSRL and LCLS, Cohen said, drawing upon key areas of expertise for SSRL and the unique capabilities of LCLS. “The combined effort of staff at both experimental facilities was key in this success,” she said.

    In addition to staff at SLAC’s SSRL and LCLS and at Stanford University’s School of Medicine, researchers from SLAC’s Photon Science Directorate, the University of Pittsburgh School of Medicine, Howard Hughes Medical Institute, Montana State University, Lawrence Berkeley National Laboratory and the University of California, San Francisco also participated in this effort.

    The work was supported by the Department of Energy Office of Basic Energy Sciences, the SSRL Structural Molecular Biology Program via the DOE Office of Biological and Environmental Research, and the Biomedical Technology Research Resources program at the National Institute of General Medical Sciences, National Institutes of Health.

    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 9:05 am on November 20, 2014 Permalink | Reply
    Tags: , , Biology,   

    From AAAS: “Body’s bacteria may keep our brains healthy” 

    AAAS

    AAAS

    19 November 2014
    Elizabeth Pennisi

    The microbes that live in your body outnumber your cells 10 to one. Recent studies suggest these tiny organisms help us digest food and maintain our immune system. Now, researchers have discovered yet another way microbes keep us healthy: They are needed for closing the blood-brain barrier, a molecular fence that shuts out pathogens and molecules that could harm the brain.

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    Lacking a strong blood-brain barrier, germ-free mice (left) can’t prevent a radioactive tracer (yellow) from entering the brain the way that mice with microbes (middle) can. But adding microbes to germ-free mice (right) restores the blood-brain barrier. (Miklós Tóth/Karolinkska Institutet)

    The findings suggest that a woman’s diet or exposure to antibiotics during pregnancy may influence the development of this barrier. The work could also lead to a better understanding of multiple sclerosis, in which a leaky blood-brain barrier may set the stage for a decline in brain function.

    The first evidence that bacteria may help fortify the body’s biological barriers came in 2001. Researchers discovered that microbes in the gut activate genes that code for gap junction proteins, which are critical to building the gut wall. Without these proteins, gut pathogens can enter the bloodstream and cause disease.

    In the new study, intestinal biologist Sven Pettersson and his postdoc Viorica Braniste of the Karolinska Institute in Stockholm decided to look at the blood-brain barrier, which also has gap junction proteins. They tested how leaky the blood-brain barrier was in developing and adult mice. Some of the rodents were brought up in a sterile environment and thus were germ-free, with no detectable microbes in their bodies. Braniste then injected antibodies—which are too big to get through the blood-brain barrier—into embryos developing within either germ-free moms or moms with the typical microbes, or microbiota.

    The studies showed that the blood-brain barrier typically forms a tight seal a little more than 17 days into development. Antibodies infiltrated the brains of all the embryos younger than 17 days, but they continued to enter the brains of embryos of germ-free mothers well beyond day 17, the team reports online today in Science Translational Medicine. Embryos from germ-free mothers also had fewer intact gap junction proteins, and gap junction protein genes in their brains were less active, which may explain the persistent leakiness. (The researchers didn’t look at the mice’s guts.)

    Germ-free mice even have leaky blood-brain barriers as adults. But those leaks closed after the researchers gave the animals the microbes from normal mice for 2 weeks, Pettersson says.

    The microbes have “a striking effect,” says Elaine Hsiao, a neurobiologist at the California Institute of Technology in Pasadena who was not involved in the study. The work suggests “a role for the [microbes] in regulating brain development and function.”

    But how? In the gut, bacteria may influence the gut wall’s integrity through one of their byproducts, energy-laden molecules called short-chain fatty acids. So Pettersson and his colleagues infected germ-free mice with either bacteria that made these fatty acids or ones that did not. The blood-brain barrier improved only when the bacteria made these fatty acids, Pettersson says. He thinks that these molecules may get into the blood and stimulate gene activity that leads to the closure of the barrier.

    The study is not perfect, Hsaio says. “Germ-free mice are useful tools for studying the microbiota, but the germ-free condition is artificial and involves widespread disruptions” in how the body functions, such as impaired immunity and loss of gut integrity. So these results in germ-free mice need to be confirmed in humans, she says.

    But at the very least, the findings point toward a new understanding of human health and disease, says Lora Hooper, an immunologist at the University of Texas Southwestern Medical Center in Dallas who was not involved in the work. With multiple sclerosis, neurobiologists are at a loss to explain why the disease progresses so erratically, so the idea that changes in the body’s microbes may alter the blood-brain barrier to make the brain more vulnerable to damage is appealing, Pettersson notes.

    Scientists, Hooper adds, should also investigate whether microbes help spur the development of the human fetus’s blood-brain barrier. It could be that taking antibiotics at the wrong time during pregnancy is creating abnormalities in the blood-brain barrier of the child, she says.

    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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  • richardmitnick 5:16 pm on November 19, 2014 Permalink | Reply
    Tags: , Biology, , ,   

    From Princeton: “Unique sense of ‘touch’ gives a prolific bacterium its ability to infect anything” 

    Princeton University
    Princeton University

    November 19, 2014
    Morgan Kelly, Office of Communications

    New research has found that one of the world’s most prolific bacteria manages to afflict humans, animals and even plants by way of a mechanism not before seen in any infectious microorganism — a sense of touch. This unique ability helps make the bacteria Pseudomonas aeruginosa ubiquitous, but it also might leave these antibiotic-resistant organisms vulnerable to a new form of treatment.

    Pseudomonas is the first pathogen found to initiate infection after merely attaching to the surface of a host, Princeton University and Dartmouth College researchers report in the journal the Proceedings of the National Academy of Sciences. This mechanism means that the bacteria, unlike most pathogens, do not rely on a chemical signal specific to any one host, and just have to make contact with any organism that’s ripe for infection.

    The researchers found, however, that the bacteria could not infect another organism when a protein on their surface known as PilY1 was disabled. This suggests a possible treatment that, instead of attempting to kill the pathogen, targets the bacteria’s own mechanisms for infection.

    b
    A study led by Princeton University researchers found that one of the world’s most prolific bacteria, Pseudomonas aeruginosa, manages to afflict humans, animals and even plants by way of a mechanism not before seen in any infectious microorganism — a sense of touch. This technique means the bacteria, unlike most pathogens, do not rely on a chemical signal specific to any one host. To demonstrate the bacteria’s versatility, the researchers infected ivy cells (blue rings) with the bacteria (green areas) then introduced amoebas (yellow) to the same sample. Pseudomonas immediately detected and quickly overwhelmed the amoebas. (Image by Albert Siryaporn, Department of Molecular Biology)

    Corresponding author Zemer Gitai, a Princeton associate professor of molecular biology, explained that the majority of bacteria, viruses and other disease-causing agents depend on “taste,” as in they respond to chemical signals unique to the hosts with which they typically co-evolved. Pseudomonas, however, through their sense of touch, are able to thrive on humans, plants, animals, numerous human-made surfaces, and in water and soil. They can cause potentially fatal organ infections in humans, and are the culprit in many hospital-acquired illnesses such as sepsis. The bacteria are largely unfazed by antibiotics.

    “Pseudomonas’ ability to infect anything was known before. What was not known was how it’s able to detect so many types of hosts,” Gitai said. “That’s the key piece of this research — by using this sense of touch, as opposed to taste, Pseudomonas can equally identify any kind of suitable host and initiate infection in an attempt to kill it.”

    The researchers found that only two conditions must be satisfied for Pseudomonas to launch an infection: Surface attachment and “quorum sensing,” a common bacterial mechanism wherein the organisms can detect that a large concentration of their kind is present. The researchers focused on the surface-attachment cue because it truly sets Pseudomonas apart, said Gitai, who worked with first author Albert Siryaporn, a postdoctoral researcher in Gitai’s group; George O’Toole, a professor of microbiology and immunology at Dartmouth; and Sherry Kuchma, a senior scientist in O’Toole’s laboratory.

    To demonstrate the bacteria’s wide-ranging lethality, Siryaporn infected ivy cells with the bacteria then introduced amoebas to the same sample; Pseudomonas immediately detected and quickly overwhelmed the single-celled animals. “The bacteria don’t know what kind of host it’s sitting on,” Siryaporn said. “All they know is that they’re on something, so they’re on the offensive. It doesn’t draw a distinction between one host or another.”

    When Siryaporn deleted the protein PilY1 from the bacteria’s surface, however, the bacteria lost their ability to infect and thus kill the test host, an amoeba. “We believe that this protein is the sensor of surfaces,” Siryaporn said. “When we deleted the protein, the bacteria were still on a surface, but they didn’t know they were on a surface, so they never initiated virulence.”

    Because PilY1 is on a Pseudomonas bacterium’s surface and required for virulence, it presents a comprehensive and easily accessible target for developing drugs to treat Pseudomonas infection, Gitai said. Many drugs are developed to target components in a pathogen’s more protected interior, he said.

    The video [included], captured during a span of 113 minutes, shows that Pseudomonas (gray tubes) grow exponentially — doubling their numbers roughly every 30 minutes — and establish large populations of cells over the course of a few hours. In contrast, eukaryotic organisms such as the amoeba (large organisms) grow much more slowly and can be quickly overwhelmed by a bacterial population. The bacteria’s ability to rapidly multiply in a variety hosts makes a Pseudomonas infection difficult to treat using antibiotics. (Video by Albert Siryaporn, Department of Molecular Biology)

    KC Huang, a Stanford University associate professor of bioengineering, said that the research is an important demonstration of an emerging approach to treating pathogens — by disabling rather than killing them.

    “This work indicates that the PilY1 sensor is a sort of lynchpin for the entire virulence response, opening the door to therapeutic designs that specifically disrupt the mechanical cues for activating virulence,” said Huang, who is familiar with the research but had no role in it.

    “This is a key example of what I think will become the paradigm in antivirals and antimicrobials in the future — that trying to kill the microbes is not necessarily the best strategy for dealing with an infection,” Huang said. “[The researchers'] discovery of the molecular factor that detects the mechanical cues is critical for designing such compounds.”

    Targeting proteins such as PilY1 offers an avenue for combating the growing problem of antibiotic resistance among bacteria, Gitai said. Disabling the protein in Pseudomonas did not hinder the bacteria’s ability to multiply, only to infect.

    Antibiotic resistance results when a drug kills all of its target organisms, but leaves behind bacteria that developed a resistance to the drug. These mutants, previously in the minority, multiply at an astounding rate — doubling their numbers roughly every 30 minutes — and become the dominant strain of pathogen, Gitai said. If bacteria had their ability to infect disabled, but were not killed, the mutant organisms would be unlikely to take over, he said.

    “I’m very optimistic that we can use drugs that target PilY1 to inhibit the whole virulence process instead of killing off bacteria piecemeal,” Gitai said. “This could be a whole new strategy. Really what people should be doing is screening drugs that inhibit virulence but preserve growth. This protein presents a possible route by which to do that.”

    PilY1 also is found in other bacteria with a range of hosts, Gitai said, including Neisseria gonorrhoeae or the large bacteria genus Burkholderia, which, respectively, cause gonorrhea in humans and are, along with Pseudomonas, a leading cause of lung infection in people with cystic fibrosis. It is possible that PilY1 has a similar role in detecting surfaces and initiating infection for these other bacteria, and thus could be a treatment target.

    Frederick Ausubel, a professor of genetics at Harvard Medical School, said that the research could help explain how opportunistic pathogens are able to infect multiple types of hosts. Recent research has revealed a lot about how bacteria initiate an infection, particularly via quorum sensing and chemical signals, but the question about how that’s done across a spectrum of unrelated hosts has remained unanswered, said Ausubel, who is familiar with the research but had no role in it.

    “A broad host-range pathogen such as Pseudomonas cannot rely solely on chemical cues to alert it to the presence of a suitable host,” Ausubel said.

    “It makes sense that Pseudomonas would use surface attachment as one of the major inputs to activating virulence, especially if attachment to surfaces in general rather than to a particular surface is the signal,” he said. “There is probably an advantage to activating virulence only when attached to a host cell, and it is certainly possible that other broad host-range opportunistic pathogens utilize a similar strategy.”

    The paper, Surface attachment induces Pseudomonas aeruginosa virulence, was published online Nov. 10 by the Proceedings of the National Academy of Sciences. The work was supported by a National Institutes of Health Director’s New Innovator Award (grant no. 1DP2OD004389); the National Science Foundation (grant no. 1330288); an NIH National Institute of Allergy and Infectious Diseases postdoctoral fellowship (no. F32AI095002) and grant (no. R37-AI83256-06); and the Human Frontiers in Science Program.

    See the full article, with video, here.

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    About Princeton: Overview

    Princeton University is a vibrant community of scholarship and learning that stands in the nation’s service and in the service of all nations. Chartered in 1746, Princeton is the fourth-oldest college in the United States. Princeton is an independent, coeducational, nondenominational institution that provides undergraduate and graduate instruction in the humanities, social sciences, natural sciences and engineering.

    As a world-renowned research university, Princeton seeks to achieve the highest levels of distinction in the discovery and transmission of knowledge and understanding. At the same time, Princeton is distinctive among research universities in its commitment to undergraduate teaching.

    Today, more than 1,100 faculty members instruct approximately 5,200 undergraduate students and 2,600 graduate students. The University’s generous financial aid program ensures that talented students from all economic backgrounds can afford a Princeton education.

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  • richardmitnick 7:25 pm on November 17, 2014 Permalink | Reply
    Tags: , Biology, ,   

    From SLAC: “SLAC X-ray Laser Brings Key Cell Structures into Focus” 


    SLAC Lab

    November 17, 2014

    Experiment is Important Step Toward Atomic-Scale Imaging of Intact Biological Particles

    Scientists have made high-resolution X-ray laser images of an intact cellular structure much faster and more efficiently than ever possible before. The results are an important step toward atomic-scale imaging of intact biological particles, including viruses and bacteria.

    The technique was demonstrated at the Linac Coherent Light Source (LCLS) at the Department of Energy’s SLAC National Accelerator Laboratory and reported in the Nov. 17 issue of Nature Photonics.

    art
    A 20-sided structure from a bacterial cell, called a carboxysome, is struck by an X-ray pulse (purple) at SLAC’s Linac Coherent Light Source. (SLAC National Accelerator Laboratory)

    An international team of scientists used LCLS, a DOE Office of Science User Facility, to produce tens of thousands of high-resolution images of the tiniest individual biological particles yet studied there – 20-sided structures called carboxysomes that are found in some bacterial cells and play a major role in Earth’s life-sustaining carbon cycle. Although these structures have been studied for years, much remains unknown about their inner workings.

    New Views of Bacteria’s Carbon-conversion Engines

    “In an experiment lasting only 12 minutes, we collected many high-quality images using a very small amount of sample,” said Janos Hajdu, a professor of biophysics at Uppsala University in Sweden, which led the research. “In the future you could conceivably get results within minutes that used to take five days for certain types of samples. We showed that with the right type of instruments and detectors, you can increase the throughput of X-ray lasers by a huge amount.”

    The results bolster the aims of the LCLS Single-Particle Imaging initiative, formally launched at SLAC in October in cooperation with the international scientific community, said Christoph Bostedt, a SLAC senior staff scientist who leads the initiative with staff scientist Andy Aquila. The initiative is working toward atomic-scale imaging for many types of biological samples by identifying and addressing technical challenges at LCLS.

    “As this work demonstrates, we are already achieving imaging of single particles today, and we are working to improve upon these capabilities,” Aquila said.

    Bostedt added, “We will tackle these hurdles by working with the community. LCLS managers have committed to support this effort with dedicated experimental time.”

    Biology ‘On the Fly’

    Carboxysomes are microscopic workhorses inside cyanobacteria, which carry out photosynthesis. They pull in carbon dioxide from their surroundings and use an enzyme to convert it to forms that other living things can use. An estimated 40 percent of the organic carbon on Earth was made in these cell structures. “A better understanding of the structure and function of these cell organelles could benefit carbon-cycle research,” said Dirk Hasse of Uppsala University, one of the paper’s lead authors.

    Because they vary in size from about 90 to 140 nanometers, or billionths of a meter, in diameter, it is difficult to crystallize these tiny structures for conventional X-ray studies of their structure.

    A 2011 study by members of the same international team had studied samples of a giant virus, called Mimivirus, using a similar experimental technique that jets samples in a finely focused aerosol spray into the path of the X-ray pulses.

    In the latest study they were able to achieve better resolution, showing features as small as 18 nanometers.

    The scientists said a new design for the “aerosol injector” that shot the samples in a thin stream toward the X-ray pulses was among the key improvements that allowed them to achieve higher-resolution images. They also improved data-analysis tools that automatically sorted the 70,000 images they collected and assembled them into distinct groups. These advances lay the foundation for accurate, high-throughput structure determination for individual biological samples and other types of samples.

    The resolution achieved in this first experiment was not high enough to reveal the interior of the carboxysomes, though the team said that upgrades to higher intensity and a narrower focus of LCLS X-rays could allow far more detailed explorations of many biological samples in this size range, including small viruses. “We haven’t yet reached the limits,” said Filipe Maia of Uppsala University, who participated in the study.

    Pushing the Limits

    Max Hantke of Uppsala University, a lead author of the study, said the ultrashort pulses of X-ray lasers offer important advantages over instruments like electron microscopes that are used to study biological samples.

    For example, the X-ray laser can be used to track ultrafast processes, such as how biological samples respond to pulses of light over time. “These types of experiments are not possible with other methods,” Hantke said.

    In addition to scientists from Uppsala University and SLAC, other researchers who participated in the study were from Lawrence Berkeley National Laboratory; Kansas State University; the National University of Singapore; the University of Melbourne in Australia; University of Rome in Italy; and DESY laboratory, PNSensor, Max Planck Institute for Extraterrestrial Physics and European XFEL, all in Germany.

    This work was supported by the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the European Research Council, the Röntgen-Ångström Cluster, and Stiftelsen Olle Engkvist Byggmästare. The CAMP instrument used in the experiment was funded by the Max Planck Society.

    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 5:33 am on November 12, 2014 Permalink | Reply
    Tags: , Biology, , Food research,   

    From NOVA: “The Next Green Revolution May Rely on Microbes” 

    PBS NOVA

    NOVA

    12 Jun 2014
    Cynthia Graber

    Ian Sanders wants to feed the world. A soft-spoken Brit, Sanders studies fungus genetics in a lab at the University of Lausanne in Switzerland. But fear not, he’s not on a mad-scientist quest to get the world to eat protein pastes made from ground-up fungi. Still, he believes—he’s sure—that these microbes will be critical to meeting the world’s future food needs.

    Sanders’s eyes widen with delight and almost childlike glee when he talks about a microscopic life form called mycorrhizal fungus, his chosen lifetime research subject. Mycorrhizal fungi live in a tightly wound, mutually beneficial embrace with most plants on the planet. Years of dedication have made Sanders into one of the world’s foremost experts on the genetics of the microbe, and he recently was part of a team that sequenced the first mycorrhizal fungi genome.

    mz
    Mycorrhizal fungi colonize the tip of a root, seen here under magnification.

    Despite his drive, Sanders comes across as light-hearted as he teases and jokes with fellow researchers. But he loses his affable smile as he fires off facts about the upcoming food shortage: The world’s population is expected to increase to between 9 billion and 16 billion people. Five million people per year die of direct causes of malnutrition. Three and a half million of those are children under five. Today, we have the means to grow enough food to feed all those people, but we will most certainly need to produce more in the very near future.

    Sanders may have come up with a way to do just that. He has successfully bred custom varieties of microbes that can help plants produce more food. It’s one of the ultimate goals of farming research—more food with, he hopes, little or no environmental downside.

    We’ve been looking at the wrong set of genes.

    The question of crop productivity is increasingly fraught. People in developed countries eat an enormous amount of food, and people in developing countries are beginning to close the gap. Meanwhile, the world’s population is swelling. By 2030, the UN’s Food and Agriculture Organization predicts food demand will soar by 35%. And then there’s the accelerating impact of climate change: The IPCC’s latest report on the subject, published in March, shows that scientists are predicting a 2% decrease in crop yields per decade over the next century. Higher temperatures and longer, more dramatic swings between drought and rain mean the plants that we rely on will have a hard time weathering the strain.

    According to the FAO, most of the growth in production that we’ll need has to come from increasing yields from crop plants. Selective breeding doesn’t seem to be offering the types of dramatic yield increases seen in the past. Meanwhile, genetic engineering has yet to lead to any significant increase in yields.

    Now, many scientists are saying that we’ve been looking at the wrong set of genes. Instead of in plants, the crucial genes may reside in the galaxy of bacteria and fungi that live in the soil and throughout a plant—the kind that Sanders studies.

    Sanders’ plan is to give existing fungi-plant relationships a boost by breeding better fungi. He’s testing varieties of lab-grown microbes out in the field in tropical Colombia. There, he’s hoping to help cassava plants grow heftier roots, as these potato-like crops are a staple for nearly a billion people around the world. So far, the results show that this approach just might work.

    Belowground Microbiome

    Microbes in the soil function much like the human microbiome, which helps us break down food, access nutrients, and defend against harmful invaders. A plant’s microbiome protects it against malevolent microbes. Microbes can also communicate with one another, flashing chemical alerts that let one plant know when another nearby is under attack. Bacteria and fungi even structure the soil so that it clumps together and doesn’t blow or wash away. And, just as our human cells are outnumbered by our microbial support, the microbial genes in and near the root system alone of a healthy plant greatly eclipse those of the plant itself.

    Plants have depended on microbial assistance since they first edged out of the water onto dry land, about 450 million years ago. They lassoed photosynthetic cyanobacteria and turned them into cellular machines known as chloroplasts, which harvest the sun’s energy. Today, plants are still supported by hundreds of thousands—perhaps millions—of different species of bacteria, fungi, even viruses. In fact, the rhizosphere, the area around a plant’s roots, is considered one of the most ecologically diverse regions on the planet.

    The microbiome in the rhizosphere acts as an extension of plants’ root systems, breaking down nutrients into forms that plants can use. Mycorrhizal fungi have whisper-thin fronds, called hyphae, that reach out past the root tips to access water and nutrients the plant needs to survive. They then trade those for carbohydrates the plant provides. Scientists believe that as much as 30% of the carbon that a plant produces through photosynthesis is pushed into the soil to support an entire city of microbes.

    Though mycorrhizal fungi are just a multitude microbe species in the soil in and around plant roots, they live in symbiosis with about 80–90% of agricultural crops in a relationship hundreds of millions of years old. Mycorrhizal fungi cannot survive without plants, and most plants cannot thrive without mycorrhizal fungi.
    As much as 30% of the carbon that a plant produces supports an entire city of microbes.

    On the most basic level, scientists have known that microbes associate with plants for more than a century, but, even today, many of the details of the interactions are still unknown. Part of the challenge in teasing them out is that they’ve been nearly impossible to study. Scientists estimate that perhaps 1% of all soil microbes can be grown on a petri dish, the conventional model for such research. By only being able to study the thinnest slice of life, we’ve been missing out on a vast, complicated, messy world. It’s like trying to guess what everyone on a city block does during the day by trailing just one person.

    Recently, though, scientists have begun to get a better glimpse. Genetic analyses can help classify and understand newly discovered microbes. Big Data-style techniques, with names like metagenomics, proteomics, and transcriptomics, describe methods by which scientists can take an overall picture of the genetic diversity of life in a given region, and even what genes are active. These types of studies might not be able to describe every individual, but they can give a sense of what genes are in play. Such tools are able to do more, do it more quickly, and do it for less money nearly every year.

    In only the last few years, scientists using these tools have begun to regularly uncover new information about the crucial links between microbes and plants. They’re unraveling clues as to which bacteria, fungus, or virus performs which function. They’re discovering microbes that can help plants withstand heat and drought. And they’re dialing into the genetics to understand how the microbes do what they do, how the plants react, and even what genetic material is exchanged. There’s still a world of research to be done, however. With many millions of individuals packed into every gram of soil, it’s a daunting task.
    tending-cassava-field

    ka
    Tending a cassava field in the Amazon

    Farmers have manipulated the plant-microbe relationship, unknowingly, for thousands of years. Compost, for example, does not simply contain beneficial nutrients—it also teems with living organisms, as does animal manure. Crop rotation, too, can enhance microbial diversity. Stalks and crop remains left on the field or plowed into soil provide microbes with food. And growing particular plants together—such as the traditional grouping of bean-squash-corn in the early Americas—does the same, as each plant likely contributes a complementary set of microbes.

    But, for the most part, the tightly braided relationship hasn’t yet factored into the workings of modern agriculture. Today, if a plant needs more of anything, we just add it—water, nitrogen, phosphorus, manganese, and so on. In the 20th century, this approach produced an abundance of crops and staved off starvation for millions. But it has also soaked groundwater with nitrogen, led to algal blooms in lakes and rivers, and spawned a massive dead zone in the Gulf of Mexico. Studies show that nitrogen fertilizers can also reduce the diversity of microbial life. Pesticides can be more harmful. Even tilling cleaves fungal networks. Until recently, we knew little about how we’ve been inadvertently crippling our crops’ complicated support network.

    “Over the last hundred years in agriculture, we’ve tried to take microorganisms out of the picture. And by doing that—by disrupting the soil with tillage, by using chemical pesticides—we have greatly altered the agricultural biome,” says Rusty Rodriguez, a former microbiologist with the U.S. Geological Survey who’s now head of Adaptive Symbiotic Technologies, a company developing microbial-based seed coatings. “The efficacy of many chemicals is beginning to wane.” Bacteria and fungi, Rodriguez says, “are the next paradigm for agriculture.”
    From Switzerland to Columbia

    Sanders’ Swiss workplace is immaculately clean, and the room where the fungi are taken out for study is scrupulously sterile. Every night, all night, UV lights shine a microbe-killing glare. They destroy anything that could infect his cultures of mycorrhizal fungi.

    Over the course of Sanders’ 26-year career, he’s made a number of key discoveries about fungi genetics and reproduction. He conducted early research that demonstrated that the greater the diversity of mycorrhizal fungi in a given ecosystem, the greater the diversity of plants. And in 2008, as he delved into genetics, he proved that they don’t just reproduce by cloning—they actually exchange genetic material, both in the lab and in the field.

    This gave him an idea. If the microbes created offspring that were different from one another, Sanders thought, “you have a good chance that some will be more effective on plant growth than others.” So he came up with a plan: Take different fungi, breed them, see if any help plants out more than others. In other words, take the approach to farming that breeders have used for thousands of years and use it on fungi.
    Without human intervention, the whole system of microbial support might not be optimally tweaked to match crossbred crops.

    This is where Sanders runs into occasional criticism from some of his microbe-studying colleagues, who say that nature has already bred all the best variety of microbes. “If you use the argument from these researchers,” he counters, “then no one would have produced any plants through plant breeding, because they would have said, ‘Well, nature’s already made the best plants, and we can’t make any more that are any better than what nature has made.’ Now, of course, we know from a few thousand years of agriculture that we can make plants better by crossing them, and we can get varieties that produce bigger yields than that which we see in natural-occurring varieties of those plants in nature.” Without similar human intervention, the whole system of microbial support might not be optimally tweaked to match.

    To test out his idea, Sanders partnered with a colleague in Switzerland who was studying the genetics of the fungi-rice relationship, and who already had conducted research in a university greenhouse set up for rice cultivation. Sanders grew the fungi and allowed them to exchange genetic material and reproduce, creating genetically distinct offspring. Then, he colonized rice with these distinct lines. Sanders used rice as a matter of convenience due to his colleague’s experience, but he also knew that rice, as farmed today, tends to actually grow more poorly when inoculated with mycorrhizal fungi, making it a good test bed. He was stunned when one of the lines produced a five-fold increase in growth over the other fungal lines. “To see such a huge growth increase was very, very surprising,” he says. The greenhouse was an artificial environment, and the microbe-enhanced soil was compared to sterile soil. It in no way mimicked nature. But it proved a point.

    Around that time, Sanders got back in touch with Alia Rodriguez, an agronomist in Colombia who also had expertise in mycorrhizal fungi. They had originally met when he was one of her PhD examiners in England. He was desperate to visit Colombia and see its amazing animal and plant biodiversity for himself, so they decided to try to find a research project together.

    It happened that Colombia offered the perfect field test for his new approach. Mycorrhizal fungi are skilled at helping plants access phosphorus, a key nutrient, which plants in tropical countries have a particular problem securing. The acidity of soil there results in a chemical reaction that ties up most of the phosphate that farmers add to soil. Farmers end up paying precious money to add phosphate that plants mostly can’t use. “I always tell my students, how can we rely on a practice that is so inefficient?” Rodriguez says. “It has to change, because it cannot be sustainable.”
    experimental-cassava-fields.

    fie
    Ian Sanders and Alia Rodriguez’s experimental plots in Columbia

    Colombia is also the home of cassava, a fleshy white root. Cassava is a major staple for nearly a billion people in more than 100 countries, from Brazil to Nigeria to Thailand, who rely on it in much the same way we rely on bread or potatoes. In its various homes and in various languages, it is called cassava, yuca, manioc, balinghoy, kamoteng kahoy, tapoica-root. If you can produce more cassava, then poor communities can eat more food.

    Sanders liked the idea of breeding microbes to increase cassava production. But they still had one major stumbling block ahead. There was no practical way to transport enough pure fungus from his Swiss lab to colonize the cassava trial fields in Colombia.

    This had also been a problem for the early pioneers in the field. In earlier decades, a variety of start-ups had marketed mycorrhizal fungi transported in soil, an imperfect medium that also contained plant roots and a host of other microbes. There was no way to tell whether it contained any live, viable material, let alone a specific species. Plus, transporting enough soil for every plant root on a farm would be heavy and prohibitively expensive.

    Fortunately for Sanders and Rodriguez, a company in Spain named Mycovitro coincidentally announced the culmination of decades of research of their own: a gel that could act as a vehicle for highly concentrated, purified mycorrhizal fungi. With the gel, Sanders would know that he was only transporting the microbes he wanted. A single small bottle could provide enough fungi for an entire field. Even more importantly, the gel base was capable of growing any variation that Sanders bred in his lab. The team partnered with Mycovitro to grow Sanders’ varieties. (The company has no financial connection to Sanders’ and Rodriguez’s research, and neither of the scientists have a stake in the company. The company, however, is providing its services for free, and it will have first right of refusal to commercialize any promising new line that Sanders and Rodriguez develop.)

    With the final piece in place, Sanders and Rodriguez set their research project in motion. They headed down to Columbia to test their varieties by growing hectares of cassava along the edge of the llanos, the country’s lush, damp tropical savannah.

    Catching On

    As the pieces of Sanders and Rodriguez’ research fell into place, the field of commercially-applicable bio products was undergoing a renaissance. A few decades ago, interest in microbes and their use in agriculture flared, but most of the commercial products quickly flickered out. Most of the laboratory successes hadn’t translated to the field. One of the few agricultural microbes that did catch hold was the bacterium Rhizobium, which helps legumes access nitrogen. It’s used extensively on crops such as soy. Other microbes, such as the bacterium Bacillus, are used to protect plants from pathogens. Rhizobium and Bacillus are not the only examples on the market, but the combined market share is still a small fraction of the multibillion dollar agro-chemical industry.

    But new, more effective products have begun to emerge. Marrone Bio Innovations’ most recent pesticide, called Grandevo, was developed from a soil bacterium and is marketed to protect vegetable crops from sucking insects and mites. The company, with more than 150 patents pending, has additional products in the pipeline, including a strain of Bacillus that both controls pathogens and encourages plant growth.

    Dozens of field trials in 14 states around the U.S. are testing microbial products for corn, soybeans, wheat, barley, and rice.

    Rusty Rodriguez (no relation to Alia Rodriguez in Colombia), the head of Adaptive Symbiotic Technologies, got his start in the 1990s when he and his colleagues discovered the symbiosis between plants and fungi in Yellowstone that allowed plants to survive in temperatures as high as 150˚ F. Once he identified and isolated the fungus responsible for the plant’s heat-survival ability, he realized he could use it to help other plants survive extreme heat.

    Rodriguez dove headfirst into extremophiles, sending company employees to collect plants from extreme environments around the U.S. He’s focusing on a number of products—some are single fungi, others are communities working together—that confer a variety of benefits to agricultural plants: drought tolerance, salt tolerance, and the ability to withstand swings in temperature. His company has developed tests that rule out any potential negative impacts of the strains, such as plant damage or toxicity to animals that might snack on them. They have dozens of field trials in place in 14 states around the U.S., working with farmers who are testing their products in corn, soybeans, wheat, barley, and rice.

    Farmers have been willing partners, Rodriguez says, happy to test products that might help what can be a razor thin profit margin. But, overall, the science of applying microbial products in agriculture has been hampered by one major challenge: moving from the lab to the field. “Field work is a lot more difficult to do,” says Rodriguez. “It fails way more often.”

    Sanders and Alia Rodriguez learned the same lesson in Colombia, when the floods came.

    To the llanos

    In Columbia, Sanders and Alia Rodriguez teamed up with an agricultural college named, appropriately, they hoped, Utopia. The professors and students served as field monitors for the crops and the research. Early one morning last July, the sun barely lifting off the flat green fields, I accompanied them and a group of students as they tromped out to visit their plants. Rodriguez poked fun at Sanders’ obsession with snapping photos: “We need to be moving on!” she nudged. “Yes, yes,” he muttered, bending down to focus his lens on a spider whose web spread across the spiny leaves of a pineapple plant.

    cas
    A graduate student tends cassava in an experimental plot.

    Finally we reached the experiment. The cassava looked nearly identical, all about three feet tall, creating a waist-high carpet of broad emerald leaves glittering with droplets misted from the low, grey sky. Despite the plants’ near uniform appearance, Sanders and Rodriguez knew that underground, where the fungi were going to work, the story would be different. There, they had expected to find roots of all sizes.

    The two scientists wandered out, half obscured by foliage: Rodriguez, with tight, dark ringlets woven into a long, single braid and tucked through the back of a salmon-colored baseball cap, and Sanders, whose pale skin clearly marked him as the outsider in the group. Isabel Ceballos, the Colombian PhD student managing the project, pulled a bright pink poncho over her head to ward off the rain.

    Each of the young cassava plants had started out as six-inch sticks. The team had laid them in the earth and covered them with a shallow layer of soil. Three weeks later, when the sticks started to form root buds, the students returned and carefully squeezed a layer of fungus-filled gel beneath a portion of each plant. As the roots stretched into the soil, they pushed down through the gel, inoculating them with mycorrhizae.

    That July day in Colombia, after checking the plants in the field, Sanders, Rodriguez, and I dragged plastic chairs together. They’d cleaned up from the morning’s mud. Rodriguez had changed into a striped cotton top, and her hair cascaded in waves over to the side, revealing beaded lime green and black earrings in the shape of lizards. Sanders’ short-sleeve plaid shirt looked clean and fresh. The sun set over Utopia’s low, red-roofed buildings, and the shrill blur of insects tussled with the frogs’ boggy croaks. The air was thick and warm. Fireflies flashed languidly, slow pulses of glowing and dimming light.

    “It was a good surprise to see the experiments up and running in the field now,” says Rodriguez, relaxing into the chair. “It’s been a process to get things going here. Finally to see it happening—it’s difficult, but it’s achievable. A good feeling.”

    Early on, the team had learned that Mycovitro’s own variety of mycorrhizal fungi increased cassava yields by as much as 20%. Now their own custom, lab-grown microbes were being tested. They had two studies in the field: one in which the cassava were planted in black plastic bags, and a second later one in which the cassava were planted directly in the field, with uninnoculated cassava as a barrier. Each study would take 11 months—the full time for a cassava to reach maturity.

    The first plants in the plastic bags looked a bit sickly; they’d be harvested in October. The second experiment with the plants directly in the ground were flourishing. Those would be harvested the following spring.

    Rodriguez is generally the positive one of the pair, sure that they can find a way to work through all challenges. Sanders tends to be more cautious, more pessimistic. “In Switzerland,” he joked, “we think of every single problem that could happen, and people here in Colombia are extremely optimistic—‘No worry! It will work!’” Rodriguez laughed in response. But things were looking good. Both scientists were pleased—even excited—about what they’d seen. Rodriguez’s optimism appeared justified.

    Her sunny outlook was tested only a few weeks later. The skies of the llanos, often thick and lazy with morning drizzle, turned dark. The clouds unleashed a month’s worth of merciless rain in only 48 hours. Water swept down over the cassava. When the rains finally faded, plant matter was clogging most of the field drains. Liquid mirrors pooled across the research field. Some of the plants, their roots surrounded by water and gasping for oxygen, listed to the side.

    Ceballos, the PhD student in charge of the project, heard the news first. She panicked and ran to Rodriguez to tell her what had happened. Rodriguez panicked as well, thinking, “What are we going to do?” But she quickly regrouped. “We need data,” she told Ceballos, and then called Sanders.

    un
    Unearthing cassava roots

    After a few days, students from Utopia who were dispatched to check on the fields sent back photos. Variation 1, with the older plants trapped in plastic bags, was fine. In the second one with healthier plants, the team received an incredible turn of luck. True, many of the plants were destroyed. But almost none of them had been coated with the fungi. Instead, almost all the dead cassava were just border plants.

    Sanders was relieved. “It would have been a disaster for us,” he says, if the plants had died. It would have set the project back at least a year—and the team’s funding was due to end in the summer of 2014.

    Three months later, in October, it was time to harvest the plants in the plastic bags. Ceballos headed back to Utopia. Each day for a week, she and another graduate student worked with students, crouching down and cutting open the thick black plastic. They shoved aside the soil that clung, damp, to the roots. The cassava poked out, some thicker than others, all with pale, purplish skin, smooth and wet, peeking through the dirt. Their flesh was bright white and oozed milky droplets.

    we
    Utopia students weigh cassava roots in the field.

    The team uncovered more than a thousand roots. All were quickly weighed at Utopia. Then Ceballos hauled the best, least damaged representatives of each cassava plant back to Bogotá, nearly 800 pounds of food. She stored them in a cavernous new freezer the lab bought specifically for this purpose. Over the next few months, she tested each plant’s dry weight and evaluated its fibrousness, starch content, acid content, and other variables that attest to the overall quality.

    Sanders didn’t have high hopes for the first harvest. After all, the crops didn’t look nearly as healthy as the cassava planted straight in the field. But the results thus far have surprised—and delighted—him. The data hasn’t been published in a scientific journal yet, but, he says, “We have actually seen huge differences in the weight of the cassava roots—much larger differences than seen in the rice experiment. We thought it would work but not to such an extent.”

    Into the Mainstream

    Rusty Rodriguez’s approach is proving successful, too. In 2014, his company is releasing two products, one for rice and one for corn, and he plans to have additional products for a wider variety of crops available by 2015. Based on his company’s field research, test plants are able to tolerate more stress from swings in temperature or water availability, and they can defend themselves more effectively against pests. He says his team is now looking at helping farmers decrease the amount of fertilizer they use by employing the fungi. They’re also publishing scientific studies on their research.

    The major agricultural seed and chemical companies are taking notice. In the fall of 2013, Monsanto paid the Danish company Novozymes $300 million to form a partnership called the BioAg Alliance. Novozymes creates what they call “microbial yield and fertilizer enhancers,” among other products in a variety of sectors. The partnership strengthens Monsanto’s role in what they term “sustainable microbial technology.”

    The rest of the field seems to be following suit. The trade journal Agrow: World Crop Protection News, wrote that the biopesticide sector was finally no longer “fringe” in April of 2012, and by 2013 proclaimed that it is now an “intrinsic part of the crop protection industry.” In 2012, Bayer bought the small biopesticide company AgraQuest. Syngenta bought Pasteuria Bioscience, and also has an exclusive international deal to sell a Bacillus-based biofungicide. The FDA is testing the spraying of bacteria on tomatoes that can destroy the human-harming salmonella and prevent other forms of contamination.

    There are plenty of concerns in the field of applied microbes for agriculture. One is whether any product that is successful on one farm will be equally successful on another. Then there’s the concern about releasing microbes into new environments, which means that regulatory agencies are demanding extensive environmental tests before certifying new products.

    The Colombia team is sensitive to this, and they’re studying the existing microbial ecosystems in the presence of the new fungi. They’ve also sent a grad student into the Amazon to collect fungi from wild versions of cassava, fungi that have co-evolved with the cassava for thousands of years, in hopes that they can isolate, grow, and breed these cassava-loving fungi as well.

    film
    Thin filaments of mycorrhizal fungi form a dense network between roots.

    Sanders has an ambitious, seemingly quixotic goal that he figures could be completed in 15 years, maybe 20. He wants to breed enough genetically distinct lines of fungi and try them out with enough crops in enough different environments so that researchers can create what’s called an “association map.” He would start by characterizing the genetics of the fungus and then map them against the crops and the environment. By peering deeply enough into the genetic code, he hopes we can catch a glimpse of which genes make quinoa grow better in Peru, for example. That way scientists could breed a new species of fungus and know in advance which crop it would improve without having to undertake years of trials.

    It seems nearly impossible to do enough studies, with enough crops, in enough farmland around the world to generate such a map. Genetic solutions also frequently seem to dance out of reach. Sanders insists, though, that big, crazy scientific goals in agriculture are crucial. “As one of the senior people in the Food and Agriculture Organization of the United Nations said to me, ‘If scientists don’t do that, then we are in trouble in the future.’ I believe he is right.”

    Sanders and Rodriguez are now setting up studies in Africa, where farmers, like many in Colombia, can find it difficult to pay for fertilizers and suffer from low yields. Cassava is also one of the top crops there. The team has formed partnerships with local research centers to test varieties of fungi on cassava crops in African soil. They’re hoping the research will begin soon, but they’re still searching for funding.

    The scientists believe they’re on their way to achieving their goal of helping farmers grow more food, sustainably. Says Sanders, “We really have to be working extremely hard now to produce the technology that’s going to be used in 10, 15, 20 years’ time. Even if we have something that’s good now, we don’t stop. We have to go for something that’s much better.”

    See the full article here.

    NOVA is the highest rated science series on television and the most watched documentary series on public television. It is also one of television’s most acclaimed series, having won every major television award, most of them many times over.

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  • richardmitnick 1:47 pm on November 11, 2014 Permalink | Reply
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    From DDDT at WCG: “Discovering Dengue Drugs – Together” 

    New WCG Logo

    10 Nov 2014
    By: Dr. Stan Watowich, PhD
    University of Texas Medical Branch (UTMB) in Galveston, Texas

    Summary
    For week five of our decade of discovery celebrations we’re looking back at the Discovering Dengue Drugs – Together project, which helped researchers at the University of Texas Medical Branch at Galveston search for drugs to help combat dengue – a debilitating tropical disease that threatens 40% of the world’s population. Thanks to World Community Grid volunteers, researchers have identified a drug lead that has the potential to stop the virus in its tracks.

    mic

    Dengue fever, also known as “breakbone fever”, causes excruciating joint and muscle pain, high fever and headaches. Severe dengue, known as “dengue hemorrhagic fever”, has become a leading cause of hospitalization and death among children in many Asian and Latin American countries. According to the World Health Organization (WHO), over 40% of the world’s population is at risk from dengue; another study estimated there were 390 million cases in 2010 alone.

    The disease is a mosquito-borne infection found in tropical and sub-tropical regions – primarily in the developing world. It belongs to the flavivirus family of viruses, together with Hepatitis C, West Nile and Yellow Fever.

    Despite the fact dengue represents a critical global health concern, it has received limited attention from affluent countries until recently and is widely considered to be a neglected tropical disease. Currently, no approved vaccines or treatments exist for the disease. We launched Discovering Dengue Drugs – Together on World Community Grid in 2007 to search for drugs to treat dengue infections using a computer-based discovery approach.

    In the first phase of the project, we aimed to identify compounds that could be used to develop dengue drugs. Thanks to the computing power donated by World Community Grid volunteers, my fellow researchers and I at the University of Texas Medical Branch in Galveston, Texas, screened around three million chemical compounds to determine which ones would bind to the dengue virus and disable it.

    By 2009 we had found several thousand promising compounds to take to the next stage of testing. We began identifying the strongest compounds from the thousands of potentials, with the goal of turning these into molecules that could be suitable for human clinical trials.

    We have recently made an exciting discovery using insights from Discovering Dengue Drugs – Together to guide additional calculations on our web portal for advanced computer-based drug discovery, DrugDiscovery@TACC. A molecule has demonstrated success in binding to and disabling a key dengue enzyme that is necessary for the virus to replicate.

    Furthermore, it also shows signs of being able to effectively disable related flaviviruses, such as the West Nile virus. Importantly, our newly discovered drug lead also demonstrates no negative side effects such as adverse toxicity, carcinogenicity or mutagenicity risks, making it a promising antiviral drug candidate for dengue and potentially other flavivirues. We are working with medicinal chemists to synthesize variants of this exciting candidate molecule with the goal of improving its activity for planned pre-clinical and clinical trials.

    I’d like to express my gratitude for the dedication of World Community Grid volunteers. The advances we are making, and our improved understanding of drug discovery software and its current limitations, would not have been possible without your donated computing power.

    If you’d like to help researchers make more ground-breaking discoveries like this – and have the chance of winning some fantastic prizes – take part in our decade of discovery competition by encouraging your friends to sign up to World Community Grid today. There’s a week left and the field is wide open – get started today!

    See the full article here.

    World Community Grid (WCG) brings people together from across the globe to create the largest non-profit computing grid benefiting humanity. It does this by pooling surplus computer processing power. We believe that innovation combined with visionary scientific research and large-scale volunteerism can help make the planet smarter. Our success depends on like-minded individuals – like you.”

    WCG projects run on BOINC software from UC Berkeley.

    BOINC is a leader in the field(s) of Distributed Computing, Grid Computing and Citizen Cyberscience.BOINC is more properly the Berkeley Open Infrastructure for Network Computing.

    CAN ONE PERSON MAKE A DIFFERENCE? YOU BETCHA!!

    “Download and install secure, free software that captures your computer’s spare power when it is on, but idle. You will then be a World Community Grid volunteer. It’s that simple!” You can download the software at either WCG or BOINC.

    Please visit the project pages-

    Mapping Cancer Markers
    mappingcancermarkers2

    Uncovering Genome Mysteries
    Uncovering Genome Mysteries

    Say No to Schistosoma

    GO Fight Against Malaria

    Drug Search for Leishmaniasis

    Computing for Clean Water

    The Clean Energy Project

    Discovering Dengue Drugs – Together

    Help Cure Muscular Dystrophy

    Help Fight Childhood Cancer

    Help Conquer Cancer

    Human Proteome Folding

    FightAIDS@Home

    World Community Grid is a social initiative of IBM Corporation
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  • richardmitnick 11:13 am on November 11, 2014 Permalink | Reply
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    From Pittsburgh Post Gazette: “Body temperature linked to DNA activity inside disease-causing virus” 

    ppg

    Pittsburgh Post Gazette

    November 11, 2014
    Jill Daly

    Studies by a Carnegie Mellon University lab have shown that some viruses violently expel their DNA inside human cells when the virus reaches body temperature, and that it might be possible to stop the spread of infection by interrupting that process.

    Research by CMU biophysicist Alex Evilevitch and his team demonstrated for the first time how the DNA packaged inside viruses shifts from being stiffly inflexible to becoming loose and active when the virus approaches 98.6 degrees.

    In one study involving the herpes simplex virus, which affects hundreds of millions of people worldwide, the researchers also found that negative electrical charges in the viral DNA accelerated its explosion into human cells.

    The studies raise the possibility that it might be possible to treat viral infections by controlling this transition in the mobility of viral DNA.

    Akiko Iwasaki, an immunobiology researcher at the Yale School of Medicine who was not involved in the studies, said the results suggest that “locking the viral DNA in the solid state would be beneficial in the prevention of infection. If we can find a virological agent that does that, it might be a prevention treatment.”

    Mr. Evilevitch said his lab’s fundamental discoveries about viral replication were made possible by sophisticated equipment, including an atomic force microscope that uses a minuscule needle to measure the surface features of viral DNA. Those measurements allowed the lab to discover that before the virus reaches body temperature, its DNA is still and inflexible.

    When first designing the research, about five years ago, Mr. Evilevitch said his lab was hoping to discover something about temperature’s role in the DNA transfer.

    vir
    Understanding viral infection

    “Temperature is rarely varied … in most biophysical measurements in viruses. It’s a new and rapidly developing field in virology.” New instruments are available and, he said, “a lot of times studies were done on the virus, not the single cell. We realized there were no studies on the structure of DNA in viruses, very few, and those that are done are done with cryo-electron microscopy and freezing the viruses.”

    Mr. Evilevitch said a better understanding of viruses was needed. “Before we have a medical application in mind, first we have to know how viruses work.”

    The team recently published two studies on their findings.

    In the Proceedings of the National Academy of Sciences, the team reported on their work with a virus that infects E. coli, a bacteria that can cause severe diarrhea in people. This was the one that found body temperature influenced the activity of the DNA strands.

    In Nature Chemical Biology, the team’s study of herpes simplex virus type 1 found that the similar solid-to-fluid DNA transition also occurred at body temperature, and also was linked to the ionic conditions (affecting electrical charges and the mobility of DNA strands) in epithelial and neuronal cells that are attacked by the herpes virus.

    Epithelial cells cover the inner and outer surfaces of the body and its organs; neuronal cells are in the brain, spinal cord and nerves.

    Herpes simplex virus is a challenge particularly for immune-compromised patients, such as newborn babies and cancer and HIV patients. Long-time use of antiviral medications can lead to resistance. “Mutations develop faster in immune-suppressed people,” Mr. Evilevitch said.

    The virus lies latent in neuronal cells. “The neuronal cells undergo wide variations of activity controlled by ion concentration,” he said. “We found that this affects the state of the DNA in herpes capsid, affecting the ability of the virus to release its DNA into the cell and its ability to multiply.” Virologist Fred Homa at the University of Pittsburgh School of Medicine, also participated in the study.

    Mr. Evilevitch said although the antiviral drug Acyclovir is very effective in treating herpes, “eventually the patient will develop resistance to the drug.”

    The herpes virus is challenging to get under control, agreed Yale researcher Iwasaki. “Acyclovir doesn’t cure the disease. It just prevents the replication of the virus at the time of the drug treatment. It needs to be continuously treated.”

    She added that, “Chipping away at any of these aspects of the viral life cycle is important.” Further research, she said, might shed more light on how the virus expels the DNA strands with an intense, rapid force into the host cell nucleus.

    “It might help us understand how the host might recognize, or avoid the recognition, of the virus,” she said. “Perhaps this sort of ejection of the viral DNA might be rejected by the host, somehow this might be recognized by the innate immune system.”

    See the full article here.

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  • richardmitnick 10:18 am on November 11, 2014 Permalink | Reply
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    From SLAC: “Researchers Take Snapshots of Potential ‘Kill Switch’ for Cancer” 


    SLAC Lab

    November 10, 2014

    X-ray Study Shows Protein Switch for Programmed Cell Death in Motion

    A study conducted in part at the Department of Energy’s SLAC National Accelerator Laboratory has revealed how a key human protein switches from a form that protects cells to a form that kills them – a property that scientists hope to exploit as a “kill switch” for cancer.

    The protein, called cIAP1, shields cells from programmed cell death, or apoptosis – a naturally occurring crackdown on unhealthy cells and tissues. When a cell is in trouble, a signal activates cIAP1, which rapidly transforms into a state that allows apoptosis to take place.

    cell
    The structure of cellular inhibitor-of-apoptosis protein 1 (cIAP1) in its “closed” state. The protein is a key switch for apoptosis, or programmed cell death, and is composed of four distinct domains (color coded) that rearrange depending on the position of the switch. (Allyn Schoeffler/Genentech)

    “Cancer cells produce excess amounts of cIAP1 in an attempt to shut down apoptosis and evade death,” says senior staff scientist Thomas Weiss from SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL), a DOE Office of Science User Facility, who participated in the study. “The search for drugs that would switch apoptosis back on to eradicate cancer is a very active research field.”

    The researchers used X-rays from SSRL to watch in real time how cIAP1 transitions from one state to another. The results are an important step towards becoming able to control the protein’s switching properties.

    “Our study closely ties cIAP1’s motions to its role as a switch,” says Allyn Schoeffler, a senior research associate at Genentech Inc. in South San Francisco and lead author of the study, published Nov. 10 in Nature Structural & Molecular Biology. “We now know why cIAP1 can act as a strictly controlled fail-safe for apoptosis and, at the same time, remain flexible enough to undergo rapid structural transitions.”

    Incomplete Static Model

    Earlier studies had given researchers a fairly good idea of cIAP1’s structure and general mechanism.

    In its “closed” state, which blocks apoptosis, the protein’s four parts, or domains, are tightly bound together in a rather rigid, compact structure.

    When a signal molecule binds to a specific site in cIAP1, the protein changes into its “open” state, in which the domains arrange in a more flexible, linear way. When two identical copies of this open structure partner up in what is known as a dimer, the assembly eventually self-destructs, removing the brake that blocks apoptosis and allowing cellular clean-up to carry on.

    “This model of cIAP1 action has largely been derived from static images of the protein,” Schoeffler says. “However, static pictures do not tell us the whole story.”

    Bringing Motion into the Equation

    To find out more, the research team first used a technique known as nuclear magnetic resonance spectroscopy, or NMR, to analyze how the protein domains move in the closed state, and followed up with studies at SSRL, where they observed how X-rays scatter off the transforming sample.

    scat
    Small-angle X-ray scattering models of different cIAP1 states. In its “closed” state, which blocks apoptosis, the domains are tightly bound together in a compact structure (left). Binding of a signal molecule for apoptosis switches the protein into its “open” state, in which the domains arrange in a more flexible linear way (center). When two identical copies of the open structure partner up in what is known as a dimer (right), the assembly eventually self-destructs, thereby allowing apoptosis to take place. (Allyn Schoeffler/Genentech)

    “The results showed that cIAP1 switches from ‘closed’ to ‘open’ extremely fast, within only 300 milliseconds, which we were able to determine using a technique called time-resolved small-angle X-ray scattering,” says Weiss. “The following dimer formation is even faster than that.”

    open
    Protein envelopes of cIAP1’s “open” and “closed” forms as determined by small-angle X-ray scattering (left) with detailed molecular structures modeled into them (right). For the first time, scientists have now monitored in real time how cIAP1 transitions from one state to another. (Allyn Schoeffler/Genentech)

    In addition, the scientists observed that the protein “breathes” rapidly in its closed form, with interfaces between domains opening and closing quickly.

    “The only region that is relatively rigid is the interaction site for the apoptosis signal,” says Schoeffler. “This well-defined site in the closed state allows nature to control cIAP1 very tightly. It is the critical latch that keeps the switch closed and makes sure that it does not open accidentally.”

    The rest of the protein, in contrast, is very flexible and allows cIAP1 to open instantaneously, like a spring-loaded trigger mechanism, when the proper signal is received. Once the trigger has been pulled, cell death becomes inevitable.

    Ties to Cancer Research

    The new insights could potentially benefit recent developments in cancer research. In fact, several studies are underway to explore the use of synthetic compounds that mimic nature’s signal molecules.

    “Natural and synthetic molecules are thought to interact with this protein the same way,” says Schoeffler. “Therefore, the mechanisms revealed by our study are likely to hold true in medically relevant molecules as well.”

    Research funding for the SSRL Structural Molecular Biology Program was provided by the DOE Office of Biological and Environmental Research and the National Institutes of Health, National Institute of General Medical Sciences.

    See the full article here.

    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 4:05 pm on November 8, 2014 Permalink | Reply
    Tags: , Biology, , University of Wisconsin-Madison   

    From Wisconsin: “UW team’s plants return to Earth after growing in space” 

    uw

    University of Wisconsin-Madison

    Nov. 6, 2014
    David Tenenbaum

    Researchers at Simon Gilroy’s lab in the Department of Botany at the University of Wisconsin-Madison this afternoon greeted a truck carrying small containers holding more than 1,000 frozen plants that germinated and grew aboard the International Space Station.

    two

    On Tuesday, when Gilroy’s team inspected the plants at the Kennedy Space Center in Florida, they saw exactly what they wanted: Petri dishes holding seedlings that sprouted and grew in weightlessness.

    After their arrival in Madison, the plants went directly into a deep freeze. After being thawed in a few months, they will donate their RNA to an instrument that will measure the activity of all of their approximately 30,000 genes.

    aw
    Astronaut Reid Wiseman injected a fixative solution onto the seedlings. Photo: NASA

    Half of the plants will become subjects in Gilroy’s longstanding exploration of the genetic control of the proteins that enable plants to grow in zero gravity. “Gravity is a fantastically pervasive force that affects all biology,” says Gilroy. “One astronaut observed that plants get lazy in a weightless environment; they grow long and thin, and don’t lay down strong material, just like people lose bone mass in space because it isn’t needed for supporting weight.”

    The other half of the experiment represents a departure for Gilroy, and for NASA, the agency supporting this area of space research. After these plants undergo a similar genetic analysis at UW-Madison’s Biotechnology Center, the data will get an initial check-over from Gilroy’s group. And then a treasure trove of digital data on plant genetic activity in microgravity will be made available to any researcher interested in mining it.

    “Access to space is very rare,” Gilroy says. “Traditionally, a research group will put an experiment in space, get the results and publish. But NASA is trying a new mode, called geneLAB, where the research group will put organisms in space, then, as soon as possible, release the raw data to anyone who wants to analyze it. They hope it will speed up major advances on these tiny samples that we can afford to place in space. I see this as open-source science.”

    Through the process called transcription, genes produce RNA that becomes the template for proteins, and in both sets of experiments, the RNA data will show which genes become more or less active in microgravity, when compared to an identical set of plants grown on Earth.

    plants
    Samples of Arabidopsis plants identical to those that grew in space.

    While Gilroy plans to focus on structural proteins, the geneLAB experiment compares four variants of Arabidopsis called ecotypes. “This data should provide a broad field of investigation — far more than one lab can handle,” Gilroy says. “We are going to end up with an enormous amount of transcription data. We will do some initial work to check the major genes which go up or down, but there’s tremendous potential for further analysis by other labs around the world.”

    But while the geneLab approach sounds promising, Gilroy concedes that it carries no guarantees. “This may be a path forward in crowd-sourcing science. At the least, as a single lab we could never analyze this data as fully as many labs around the world all working with it.”

    The “Biological Research in Canister” containers that held these experiments on board the space station were designed, tested and operated according to NASA’s rigorous approach, Gilroy says. “Each project represents an enormous investment, and you really want everything to go perfectly. You become one of the most careful scientists in the world. You test everything, make duplicates, and are always considering what may go wrong so you can do another test.”

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    Won-Gyu Choi settles four canisters of plants grown aboard the International Space Station into a -80 degree Celsius freezer in Birge Hall. Photo: David Tenenbaum

    NASA is an unfamiliar world to most botanists, but Gilroy seems to be enjoying every step of the way, and has even learned the organization’s peculiar parlance. “At first, talking in acronyms is very strange,” he says, “and you can’t understand anything when NASA people start going into NASA-speak. But once you get into it, you catch yourself doing the exact same thing.”

    In the microgravity experiments, Gilroy is exploring the genetic basis of a phenomenon known to gardeners and horticulturalists for many years. Plants that grow up without mechanical stresses — due to wind, rain or other disturbances — “are much more susceptible to pests, are not as robust,” Gilroy says, “but if you go into a greenhouse and shake the plants, they grow up more compact, strong, and resistant to stress. They are even more resistant to plant diseases.”

    It turns out that the same signaling system used to detect mechanical stresses like gravity is also used to defend against pathogens. That may explain why plants in space appear more susceptible to disease.

    That overlap raises the stakes for understanding the impact of gravity on plants beyond the notion of building stronger crops that can stand up in the field. Understanding the signals could help in the never ending battle against plant disease.

    Likewise, NASA has its own practical interest in the research: Plants will supply food and oxygen for long-distance space travel, and keeping them healthy will be a matter of life and death. “If you are growing plants as part of a human life support system,” Gilroy says, “you’d rather not have them suddenly die.”

    See the full article here.

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  • richardmitnick 3:42 pm on November 8, 2014 Permalink | Reply
    Tags: , Biology, , Synthetic Biology   

    From LBL: “Synthetic Biology for Space Exploration” 

    Berkeley Logo

    Berkeley Lab

    November 5, 2014
    Lynn Yarris (510) 486-5375

    Does synthetic biology hold the key to manned space exploration of the Moon and Mars? Berkeley Lab researchers have used synthetic biology to produce an inexpensive and reliable microbial-based alternative to the world’s most effective anti-malaria drug, and to develop clean, green and sustainable alternatives to gasoline, diesel and jet fuels. In the future, synthetic biology could also be used to make manned space missions more practical.

    “Not only does synthetic biology promise to make the travel to extraterrestrial locations more practical and bearable, it could also be transformative once explorers arrive at their destination,” says Adam Arkin, director of Berkeley Lab’s Physical Biosciences Division (PBD) and a leading authority on synthetic and systems biology.

    “During flight, the ability to augment fuel and other energy needs, to provide small amounts of needed materials, plus renewable, nutritional and taste-engineered food, and drugs-on-demand can save costs and increase astronaut health and welfare,” Arkin says. “At an extraterrestrial base, synthetic biology could make even more effective use of the catalytic activities of diverse organisms.”

    aa
    Adam Arkin is a leading authority on synthetic and systems biology.

    Arkin is the senior author of a paper in the Journal of the Royal Society Interface that reports on a techno-economic analysis demonstrating “the significant utility of deploying non-traditional biological techniques to harness available volatiles and waste resources on manned long-duration space missions.” The paper is titled Towards Synthetic Biological Approaches to Resource Utilization on Space Missions. The lead and corresponding author is Amor Menezes, a postdoctoral scholar in Arkin’s research group at the University of California (UC) Berkeley. Other co-authors are John Cumbers and John Hogan with the NASA Ames Research Center.

    One of the biggest challenges to manned space missions is the expense. The NASA rule-of-thumb is that every unit mass of payload launched requires the support of an additional 99 units of mass, with “support” encompassing everything from fuel to oxygen to food and medicine for the astronauts, etc. Most of the current technologies now deployed or under development for providing this support are abiotic, meaning non-biological. Arkin, Menezes and their collaborators have shown that providing this support with technologies based on existing biological processes is a more than viable alternative.

    am
    Amor Menezes

    “Because synthetic biology allows us to engineer biological processes to our advantage, we found in our analysis that technologies, when using common space metrics such as mass, power and volume, have the potential to provide substantial cost savings, especially in mass,” Menezes says.

    In their study, the authors looked at four target areas: fuel generation, food production, biopolymer synthesis, and pharmaceutical manufacture. They showed that for a 916 day manned mission to Mars, the use of microbial biomanufacturing capabilities could reduce the mass of fuel manufacturing by 56-percent, the mass of food-shipments by 38-percent, and the shipped mass to 3D-print a habitat for six by a whopping 85-percent. In addition, microbes could also completely replenish expired or irradiated stocks of pharmaceuticals, which would provide independence from unmanned re-supply spacecraft that take up to 210 days to arrive.

    “Space has always provided a wonderful test of whether technology can meet strict engineering standards for both effect and safety,” Arkin says. “NASA has worked decades to ensure that the specifications that new technologies must meet are rigorous and realistic, which allowed us to perform up-front techno-economic analysis.”

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    Microbial-based biomanufacturing could be transformative once explorers arrive at an extraterrestrial site. (Image courtesy of Royal Academy Interface)

    The big advantage biological manufacturing holds over abiotic manufacturing is the remarkable ability of natural and engineered microbes to transform very simple starting substrates, such as carbon dioxide, water biomass or minerals, into materials that astronauts on long-term missions will need. This capability should prove especially useful for future extraterrestrial settlements.

    “The mineral and carbon composition of other celestial bodies is different from the bulk of Earth, but the earth is diverse with many extreme environments that have some relationship to those that might be found at possible bases on the Moon or Mars,” Arkin says. “Microbes could be used to greatly augment the materials available at a landing site, enable the biomanufacturing of food and pharmaceuticals, and possibly even modify and enrich local soils for agriculture in controlled environments.”

    The authors acknowledge that much of their analysis is speculative and that their calculations show a number of significant challenges to making biomanufacturing a feasible augmentation and replacement for abiotic technologies. However, they argue that the investment to overcome these barriers offers dramatic potential payoff for future space programs.

    “We’ve got a long way to go since experimental proof-of-concept work in synthetic biology for space applications is just beginning, but long-duration manned missions are also a ways off,” says Menezes. “Abiotic technologies were developed for many, many decades before they were successfully utilized in space, so of course biological technologies have some catching-up to do. However, this catching-up may not be that much, and in some cases, the biological technologies may already be superior to their abiotic counterparts.”

    This research was supported by the National Aeronautics and Space Administration (NASA) and the University of California, Santa Cruz.

    See the full article here.

    A U.S. Department of Energy National Laboratory Operated by the University of California

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