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

    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 5:16 pm on November 19, 2014 Permalink | Reply
    Tags: , , Medicine, ,   

    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 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

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  • richardmitnick 11:13 am on November 11, 2014 Permalink | Reply
    Tags: , , , Medicine   

    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 1:37 pm on October 31, 2014 Permalink | Reply
    Tags: , , Medicine,   

    From NOVA: “Bioinspired Underwater Glue Could Soon Replace Stitches” 

    PBS NOVA

    NOVA

    Fri, 31 Oct 2014
    Sarah Schwartz

    It’s a sticky situation—in the best possible way. By combining proteins that mussels and bacteria use to stick to surfaces, scientists at the Massachusetts Institute of Technology have created a strong new underwater glue. This adhesive could tackle an important challenge in various fields, including surgery, where repairing wet surfaces is essential.

    For years, scientists have used marine organisms for insight in producing underwater glues. Water forms a “weak boundary” on surfaces it contacts, which prevents adhesives from attaching, says Dr. Herbert Waite, Professor of Molecular, Cellular, and Developmental Biology at the University of California, Santa Barbara. This becomes a challenge in fields where wet surfaces need to be repaired—marine salvage, dentistry, surgery, and more. But organisms like mussels and barnacles regularly overcome this obstacle, binding easily to wet rocks.

    The MIT team turned to these organisms for inspiration—and ingredients. “One of the promises in synthetic biology is to be able to mix and match and optimize biologically based materials,” says Dr. Timothy Lu, an associate professor in MIT’s Synthetic Biology group and an author of the study. Lu and his colleagues combined proteins from two different sources—the feet of mussels, and E. coli bacteria.

    mus
    By combining proteins that mussels and bacteria use to stick to surfaces, scientists at MIT have created a strong new underwater glue.

    A good adhesive has two properties, Waite says: It has to be able to stick to other surfaces, and it also has to bind to itself. DOPA, the protein mussels use to adhere to surfaces, can do both, but its behavior depends upon the conditions of its environment. Mussels use various “tricks” to control their DOPA that aren’t fully understood, Waite says. If you’re not a mussel, it can be hard to manage DOPA’s behavior.

    That’s where the second protein helps. Amyloids are also adhesive, water-resistant, and link strongly to one another. Barnacles, algae, and bacteria use them to stick to surfaces. Lu and his team saw an opportunity: “[W]e thought by combining the bacteria with the mussels, we might be able to get some synergistic behavior,” says Lu.

    The result was a glue stronger than any other bio-derived or bio-inspired adhesive made to date. Waite, who was not involved with the study, says the results “really impressed” him. The researchers only asked DOPA to work in the form where it adheres to surfaces, he explains, while the amyloid proteins held the glue together. This joint behavior gives the glue its strength.

    Lu believes that this is only the beginning. “We only looked at two of the proteins that are involved in mussel adhesion…If we could combine multiple proteins on top of that, maybe we can even get stronger performance,” he says. While the group has been focused on adhesion alone, in the future, the group plans to explore potential underwater and biomedical uses, says Lu.

    These biomedical applications could be profound, especially in surgery. Waterproof glues could help seal internal wounds, even when drenched in blood and other fluids. Sutures or staples are currently used to close such holes, but these are hard to affix and can damage tissues, says Dr. Jeffrey Karp, an associate professor at Brigham and Women’s Hospital and Harvard Medical School. Karp, who was not involved in the MIT study.

    “There’s a huge unmet need for better adhesives,” says Karp, who is also a co-founder of Gecko Biomedical, which is developing medical adhesives. “There’s really nothing available in the clinic that works well and doesn’t have its drawbacks,” he adds, calling Lu’s team’s work “excellent and very promising.” The next step, Karp says, is to test the glue at larger scales.

    To work inside the human body, an adhesive must be biocompatible, or “cell-friendly.” But strong glues are often toxic. “We really don’t have anything that is strong and biocompatible,” says Dr. Pedro del Nido, a specialist in cardiac surgery at Boston’s Children’s Hospital who was not involved with the MIT study.

    Lu says his group is interested in testing for biocompatibility and believes that natural sources will yield better biocompatible materials. Looking to nature for advice has served him well so far. “[N]ature has solved a lot of the same problems that we deal with in pretty creative ways…Often times, borrowing upon nature and then applying the tools that we have in our arsenal to improve those properties, I think, is a really powerful way to go.”

    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 4:51 pm on October 27, 2014 Permalink | Reply
    Tags: , , , Medicine, ,   

    From Mapping Cancer Markers at WCG: “Early-stage results from the Mapping Cancer Markers team” 

    New WCG Logo

    27 Oct 2014
    The Mapping Cancer Markers research team

    The Princess Margaret Cancer Foundation Mapping Cancer Markers team has nearly finished establishing their benchmarks – a crucial step for their research and other related medical research around the world. See their in-depth update for the latest news about their efforts to help predict, identify and treat cancer.

    Summary
    Thanks to your help, the Mapping Cancer Markers team is nearly finished with benchmarking their first set of genetic markers. In this update, the team presents an in-depth review of what they’ve accomplished thus far, and what significance this early work will have for cancer research at their lab and elsewhere.

    The Mapping Cancer Markers (MCM) team would like to extend a huge thank you to World Community Grid members everywhere. As of October 27, 2014, we have surpassed 89,000 years of computation, a goal that simply would not be possible without your help.

    We are happy to report that we have begun to analyze the results using a high-throughput analytics package to assess the fitness and landscape of gene signature sizes between 5 and 25 genes. This analysis has shown that smaller signatures usually comprise different genes compared to larger signatures (i.e., you cannot “build” a larger signature from small ones), and that those genes are targeting many different signaling cascades and biological processes.

    Analytics

    To get a better understanding of how much data our team is receiving, we’d like to briefly introduce one of the tools that we have adopted to analyze the incoming results. From the very beginning of the project, it was clear that analyzing such a large, ongoing flow of data would be a challenge. Thus, we started to use the IBM® InfoSphere® Streams real-time analytics platform to streamline the analysis pipeline. When complete, our Streams application will run continuously, processing members’ work units in real time as we receive them. We currently have the core analysis framework implemented and running on a subset of the MCM results. We will continue to add additional layers of analysis, and fine-tune our system until it is running at full capacity. For that reason, we have dedicated one of our main compute servers (IBM Power® 780) to analyzing MCM results.

    Results

    Pictured below is a sampling (a very small fraction) of some of the ongoing work that will establish a benchmark for further experiments. Each dot in both of the graphs is a potential lung-cancer biomarker. These graphics are distilled from thousands of MCM results sent back by World Community Grid members.

    mar

    mar2

    Most of the dots have very little significance; this is expected because not everything shuts down or is activated in cancer. In other words, the graphics show differences between the disease state and the non-disease state, so we expect some things to be different, but not everything. For those reasons, most biomarkers cannot significantly differentiate cancer from non-cancer samples – this is represented by the haze of dots along the zero line. We show two graphs to illustrate the difference between shorter and longer gene signatures. Some genes that are more predictive in the shorter signature sizes do not necessarily hold their predictive power when considering more genes per signature. Most importantly, in each analysis, a few biomarkers frequently appear in high-scoring signatures. Our analysis wades through massive amounts of data to recognize those few markers that stand out.

    The first half of the “benchmarking” experiment involves determining the performance of markers as the size of the signature changes. For instance, when we compare successful 5-marker signatures against 20-marker signatures, which markers are consistently useful? Which ones increase or diminish in predictive power? Is there an optimum size for signatures? And most importantly, can we identify seemingly minor players that are critical, but not yet in clinical use that can discriminate between normal and disease states?

    graph

    After surveying the first several billion signatures, we have identified the highest-ranking combinations and underlying single genes. After separating those genes by signature size, we can see how some genes remain important regardless of the size, and how other genes “appear” to be important but are only showing up as single events. Considering we have not yet analyzed the complete data set, we have identified the genes by their known functions rather than names, to eliminate any bias towards known markers. However, even by their functions, we can see that many important signaling cascades and biological processes are affected. The most notable of these is “Cellular Fate and Organization”, which makes sense. Sometimes, when an organism loses the ability to naturally kill defective cells, it leads to uncontrolled growth, one of the hallmarks of cancer.

    Network Analysis of Major Genes:

    To further analyze the nature of our top-performing genes, we can identify their inter-relations in biological networks. We currently maintain one of the largest curated protein-protein interaction databases, which enables us to determine whether our genes (when converted to proteins) are known to interact with other important biomarkers, and in turn, what biological processes may be involved. The graph below shows one such network; nodes in the graph represent genes, edges are physical protein interactions. Node color highlights biological function as described in the legend. Use of biological networks can reveal very small subtleties of how the mechanisms of disease function and elucidate how our proteins may be causing problems; thus, eventually leading to understanding how cancer starts, progresses and how can we treat it.

    tre

    In the above network, 20 out of 24 important proteins we have identified on World Community Grid (right hand side) can be linked through known protein interactions and 56 other proteins (left hand side). We have also conducted a short analysis of the 4 proteins not yet identified using a software prediction package and found those to have significant partners. Those interactions will be evaluated in the near future. The 20 proteins noted above, strikingly, do not interact directly, however, 4 of them show very high interactivity, and can be considered as hubs. From other analyses we know that “hub proteins” are often critical, as they affect many signaling cascades and biological processes. When such proteins malfunction, catastrophic changes often result. On the other hand, proteins with low interactivity could be useful as clinical biomarkers. If they are known to only interact with a few other proteins, then their activity may help to identify particular states of cancer, while having less background “noise”. As a whole we can see that for the most part, our genes of interest are targeting mostly “genome maintenance” and “cellular fate and organization” proteins, which make up about 70% of the interacting proteins (left hand side). This is a good indication that most of the pathways affected are in those major categories, which is consistent with how we understand lung cancer to progress.

    Funding & Fundraising:

    This past August, we completed our 4th successful Team Ian Ride for Cancer Informatics Research. We were able to raise over $80,000 for cancer research in the name of a former Jurisica student, Ian Van Toch.

    Part of this funding is used for the best student paper award at the ISMB conference, and for supporting Cancer Informatics interns.

    We also support a special seminar series at Princess Margaret Cancer Center, and the recent presentation by Dr. Wan Lam from BC Cancer Agency discussed “Multi-dimensional Analysis of Lung Cancer Genomes”.

    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 3:04 pm on October 20, 2014 Permalink | Reply
    Tags: , , , Medicine   

    From LLNL: “Supercomputers link proteins to drug side effects” 


    Lawrence Livermore National Laboratory

    10/20/2014
    Kenneth K Ma, LLNL, (925) 423-7602, ma28@llnl.gov

    New medications created by pharmaceutical companies have helped millions of Americans alleviate pain and suffering from their medical conditions. However, the drug creation process often misses many side effects that kill at least 100,000 patients a year, according to the journal Nature.

    Lawrence Livermore National Laboratory researchers have discovered a high-tech method of using supercomputers to identify proteins that cause medications to have certain adverse drug reactions (ADR) or side effects. They are using high-performance computers (HPC) to process proteins and drug compounds in an algorithm that produces reliable data outside of a laboratory setting for drug discovery.

    The team recently published its findings in the journal PLOS ONE, titled Adverse Drug Reaction Prediction Using Scores Produced by Large-Scale Drug-Protein Target Docking on High-Performance Computer Machines.

    “We need to do something to identify these side effects earlier in the drug development cycle to save lives and reduce costs,” said Monte LaBute, a researcher from LLNL’s Computational Engineering Division and the paper’s lead author.

    It takes pharmaceutical companies roughly 15 years to bring a new drug to the market, at an average cost of $2 billion. A new drug compound entering Phase I (early stage) testing is estimated to have an 8 percent chance of reaching the market, according to the Food and Drug Administration (FDA).

    A typical drug discovery process begins with identifying which proteins are associated with a specific disease. Candidate drug compounds are combined with target proteins in a process known as binding to determine the drug’s effectiveness (efficacy) and/or harmful side effects (toxicity). Target proteins are proteins known to bind with drug compounds in order for the pharmaceutical to work.

    While this method is able to identify side effects with many target proteins, there are myriad unknown “off-target” proteins that may bind to the candidate drug and could cause unanticipated side effects.

    Because it is cost prohibitive to experimentally test a drug candidate against a potentially large set of proteins — and the list of possible off-targets is not known ahead of time — pharmaceutical companies usually only test a minimal set of off-target proteins during the early stages of drug discovery. This results in ADRs remaining undetected through the later stages of drug development, such as clinical trials, and possibly making it to the marketplace.

    There have been several highly publicized medications with off-target protein side effects that have reached the marketplace. For example, Avandia, an anti-diabetic drug, caused heart attacks in some patients; and Vioxx, an anti-inflammatory medication, caused heart attacks and strokes among certain patient populations. Both therapeutics were recalled because of their side effects.

    “There were no indications of side effects of these medications in early testing or clinical trials,” LaBute said. “We need a way to determine the safety of such therapeutics before they reach patients. Our work can help direct such drugs to patients who will benefit the most from them with the least amount of side effects.”

    LaBute and the LLNL research team tackled the problem by using supercomputers and information from public databases of drug compounds and proteins. The latter included protein databases of DrugBank, UniProt and Protein Data Bank (PDB), along with drug databases from the FDA and SIDER, which contain FDA-approved drugs with ADRs.

    The team examined 4,020 off-target proteins from DrugBank and UniProt. Those proteins were indexed against the PDB, which whittled the number down to 409 off-proteins that have high-quality 3D crystallographic X-ray diffraction structures essential for analysis in a computational setting.

    mp

    The 409 off-target proteins were fed into a Livermore HPC software known as VinaLC along with 906 FDA-approved drug compounds. VinaLC used a molecular docking matrix that bound the drugs to the proteins. A score was given to each combination to assess whether effective binding occurred.

    The binding scores were fed into another computer program and combined with 560 FDA-approved drugs with known side effects. An algorithm was used to determine which proteins were associated with certain side effects.

    The Lab team showed that in two categories of disorders — vascular disorders and neoplasms — their computational model of predicting side effects in the early stages of drug discovery using off-target proteins was more predictive than current statistical methods that do not include binding scores.

    In addition to LLNL ADR prediction methods performing better than current prediction methods, the team’s calculations also predicted new potential side effects. For example, they predicted a connection between a protein normally associated with cancer metastasis to vascular disorders like aneurysms. Their ADR predictions were validated by a thorough review of existing scientific data.

    “We have discovered a very viable way to find off-target proteins that are important for side effects,” LaBute said. “This approach using HPC and molecular docking to find ADRs never really existed before.”

    The team’s findings provide drug companies with a cost-effective and reliable method to screen for side effects, according to LaBute. Their goal is to expand their computational pharmaceutical research to include more off-target proteins for testing and eventually screen every protein in the body.

    “If we can do that, the drugs of tomorrow will have less side effects that can potentially lead to fatalities,” Labute said. “Optimistically, we could be a decade away from our ultimate goal. However, we need help from pharmaceutical companies, health care providers and the FDA to provide us with patient and therapeutic data.”

    two
    LLNL researchers Monte LaBute (left) and Felice Lightstone (right) were part of a Lab team that recently published an article in PLOS ONE detailing the use of supercomputers to link proteins to drug side effects. Photo by Julie Russell/LLNL

    The LLNL team also includes Felice Lightstone, Xiaohua Zhang, Jason Lenderman, Brian Bennion and Sergio Wong.

    See the full article here.

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  • richardmitnick 2:46 pm on October 17, 2014 Permalink | Reply
    Tags: , Medicine,   

    From NOVA: “Insulin-Producing Stem Cells Could Provide Lasting Diabetes Treatments” 

    PBS NOVA

    NOVA

    Fri, 17 Oct 2014
    Sarah Schwartz

    Researchers have crafted what may be a powerful weapon in the fight against diabetes: A new line of insulin-producing cells that has been shown to reverse diabetes in mice within forty days. Scientists hope that these cells may someday do the same in humans.

    The new cells, called “Stage 7” or “S7” for their seven-step production process, are the product of a study by researchers at the University of British Columbia and the pharmaceutical company Janssen. S7 cells are made to mimic human beta cells, which are damaged or destroyed in patients with diabetes. Healthy beta cells produce insulin and help regulate blood sugar; S7 cells are grown from human embryonic stem cells and are programmed to do the same.

    cells
    A microscopic view of beta cells derived from stem cells

    “The advance that they have made is that they’ve got better cells in the test tube, cells that have more insulin and can secrete insulin in response to glucose,” said Dr. Gordon Weir, a physician and researcher at Joslin Diabetes Center and Harvard Medical School. “People haven’t been able to do that before.”

    Human embryonic stem cells, like those used to produce the S7 line, show great promise for producing beta cell replacements. Just last week, another team of researchers led by Dr. Douglas Melton at Harvard University announced their own line of insulin-producing cells, also produced from human embryonic stem cells. Like S7 cells, the Harvard team’s cells produce insulin in response to high blood sugar and can reverse diabetes symptoms in mice.

    The hope is that cells like these could be injected into diabetic patients, restoring normal beta cell function. Timothy Kieffer, head of the diabetes research group at University of British Columbia and a co-author of the S7 cell study, said that treatment with these cells could be curative, though other researchers caution that additional work has to be done before that’s the case.

    Cellular transplantation has already been shown to effectively combat diabetes. Since the late 1980s, beta cells extracted from cadaver pancreases have been used to normalize blood sugar in diabetics. But these treatments are not an option for many patients. In addition to the challenges of establishing a treatment program, Weir said, “there aren’t enough pancreatic donors to even scratch the surface.” These transplanted cells also tend to stop working over time, said Dr. David Nathan, the director of the Diabetes Center and Clinical Research Center at Massachusetts General Hospital. Whole organ pancreatic transplants usually last longer and have been increasingly successful in recent years, Nathan says. But both organ and cell transplants from cadavers require immunosuppressive treatments, which can cause tumors, skin cancers, and weakened immune systems.

    Beta cells grown from stem cells could solve some of these problems. It is possible that stem cells could be developed to reduce or eliminate the need for immunosuppression, Nathan said. Plus, their supply is theoretically unlimited. “If you can make them in a test tube, in a dish, whatever—well, that gets rid of the problem of donor pancreases,” Nathan said. While S7 cells are most efficient when made from human embryonic stem cells, they can also be made using induced pluripotent stem cells, which are reprogrammed adult cells. This, Weir noted, could eliminate “ethical issues” involved with embryonic stem cell use.

    Kieffer believes that a stem cell-based treatment would also be superior to insulin supplementation, the current standard of treatment for type 1 diabetes. In type 1 diabetes, which Kieffer’s research targets, beta cells are destroyed by an autoimmune attack, and patients require external insulin to survive. Even with advanced treatment options like insulin pumps, Weir said, it is challenging to keep blood sugar in a normal range. “And if you push hard enough to drive the blood sugar down, you end up getting into trouble with insulin reactions,” Weir said. “The blood sugar goes too low and that’s dangerous.”

    But S7 cells have some challenges to overcome before they can replace current treatments. For one, it can be difficult to control the development of stem cells, Nathan pointed out. Kieffer agreed that more research is needed to mature the cells, which are still not identical to human beta cells because they react more slowly to sugar and don’t release as much insulin. Kieffer’s collaborators are also working to scale up production of the S7 line. Meanwhile, the Harvard study uses a protocol that already seems to allow relatively large-scale development of insulin-producing cells.

    There are also other challenges to treating type 1 diabetes with cells like S7 because of the autoimmune nature of the disease. If beta cell transplants are injected into type 1 diabetics, Weir said, “those cells are still going to be subject to the immune problem that killed the cells in the first place.” Kieffer said that the “next hurdle” for his team is to see if S7 cells will work inside devices that prevent immune attack.

    These “immunobarrier” devices are essentially capsules that contain implanted stem cells, allowing the exchange of nutrients and insulin while blocking attacking immune cells. Nathan and Weir expressed reservations about these devices. Nathan wondered if they can be designed to allow sufficient blood flow and nutrients to all the cells inside, while Weir questioned whether there could be a device large enough to hold the number of cells needed to control the disease. Still, in August, the company Viacyte started clinical trials with such a device, using a line of cells less developed than S7. “We’ll have to wait and see,” Weir said.

    Because of the autoimmunity problem inherent in type 1 diabetes, Weir says that it may be easier to use beta cell transplantations to treat type 2 diabetes instead. Up to 95% of diabetic patients have this form of the disease, which involves no autoimmunity. Instead, in type 2, beta cells “wear out” such that the body stops responding to insulin.

    “You can take a type 2 diabetic and give them insulin injections and normalize the sugar if you do it carefully,” Weir said. “So, a beta cell transplant is just the same thing as giving an insulin injection.” He feels the effects of such treatment could be profound. “You can put cells in and normalize the blood sugar for years,” he said. “So if you want to call that a cure, I’d go along with that.” Nathan disagrees: because type 2 diabetics have some pancreatic function, it can be simpler and easier to treat their symptoms. Because of this, he believes that cellular transplantations will mostly be useful to combat type 1 diabetes.

    Nathan doesn’t think that beta cell transplantations are an “appropriate clinical option”—yet. “The balance between risk and benefit isn’t quite right,” he says. Still, he hopes that someday, a cellular treatment will be advanced enough to safely and effectively treat this disease. “To cure type 1 diabetes would be a godsend,” he says. “To actually do a single procedure that essentially takes away the disease at low risk would be great.”

    Though several questions must be answered before they start curing patients, S7 cells are a promising step in the fight against a disease that affects 347 million people worldwide. The field is moving quickly towards its goal; as Kieffer writes, “I am very optimistic that we are narrowing down on a cure for diabetes.”

    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 8:38 am on October 17, 2014 Permalink | Reply
    Tags: , , Medicine, ,   

    From UC Berkeley: “New front in war on Alzheimer’s, other protein-folding diseases” 

    UC Berkeley

    UC Berkeley

    October 16, 2014
    Robert Sanders

    A surprise discovery that overturns decades of thinking about how the body fixes proteins that come unraveled greatly expands opportunities for therapies to prevent diseases such as Alzheimer’s and Parkinson’s, which have been linked to the accumulation of improperly folded proteins in the brain.

    “This finding provides a whole other outlook on protein-folding diseases; a new way to go after them,” said Andrew Dillin, the Thomas and Stacey Siebel Distinguished Chair of Stem Cell Research in the Department of Molecular and Cell Biology and Howard Hughes Medical Institute investigator at the University of California, Berkeley.

    br
    A cell suffering heat shock is like a country besieged, where attackers first sever lines of communications. The pat-10 gene helps repair communication to allow chaperones to treat misfolded proteins. (Andrew Dillin graphic)

    Dillin, UC Berkeley postdoctoral fellows Nathan A. Baird and Peter M. Douglas and their colleagues at the University of Michigan, The Scripps Research Institute and Genentech Inc., will publish their results in the Oct. 17 issue of the journal Science.

    Cells put a lot of effort into preventing proteins – which are like a string of beads arranged in a precise three-dimensional shape – from unraveling, since a protein’s activity as an enzyme or structural component depends on being properly shaped and folded. There are at least 350 separate molecular chaperones constantly patrolling the cell to refold misfolded proteins. Heat is one of the major threats to proteins, as can be demonstrated when frying an egg – the clear white albumen turns opaque as the proteins unfold and then tangle like spaghetti.

    Heat shock

    For 35 years, researchers have worked under the assumption that when cells undergo heat shock, as with a fever, they produce a protein that triggers a cascade of events that field even more chaperones to refold unraveling proteins that could kill the cell. The protein, HSF-1 (heat shock factor-1), does this by binding to promoters upstream of the 350-plus chaperone genes, upping the genes’ activity and launching the army of chaperones, which originally were called “heat shock proteins.”

    Injecting animals with HSF-1 has been shown not only to increase their tolerance of heat stress, but to increase lifespan.

    Because an accumulation of misfolded proteins has been implicated in aging and in neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s diseases, scientists have sought ways to artificially boost HSF-1 in order to reduce the protein plaques and tangles that eventually kill brain cells. To date, such boosters have extended lifespan in lab animals, including mice, but greatly increased the incidence of cancer.

    Dillin’s team found in experiments on the nematode worm C. elegans that HSF-1 does a whole lot more than trigger release of chaperones. An equal if not more important function is to stabilize the cell’s cytoskeleton, which is the highway that transports essential supplies – healing chaperones included – around the cell.

    “We are suggesting that, rather than making more of HSF-1 to prevent diseases like Huntington’s, we should be looking for ways to make the actin cytoskeleton better,” Dillin said. Such tactics might avoid the carcinogenic side effects of upping HSF-1.

    Dillin is codirector of the Paul F. Glenn Center for Aging Research, a new collaboration between UC Berkeley and UC San Francisco supported by the Glenn Foundation for Medical Research. Center investigators will study the many ways that proteins malfunction within cells, ideally paving the way for novel treatments for neurodegenerative diseases.

    A cell at war

    Dillin compares a cell experiencing heat shock to a country under attack. In a war, an aggressor first cuts off all communications, such as roads, train and bridges, which prevents the doctors from treating the wounded. Similarly, heat shock disrupts the cytoskeletal highway, preventing the chaperone “doctors” from reaching the patients, the misfolded proteins.

    chap
    Chaperones help newborn proteins (polypeptides) fold properly, but also fix misfolded proteins.

    “We think HSF-1 not only makes more chaperones, more doctors, but also insures that the roadways stay intact to keep everything functional and make sure the chaperones can get to the sick and wounded warriors,” he said.

    The researchers found specifically that HSF-1 up-regulates another gene, pat-10, that produces a protein that stabilizes actin, the building blocks of the cytoskeleton.

    By boosting pat-10 activity, they were able to cure worms that had been altered to express the Huntington’s disease gene, and also extend the lifespan of normal worms.

    Dillin suspects that HSF-1’s main function is, in fact, to protect the actin cytoskeleton. He and his team mutated HSF-1 so that it no longer boosted chaperones, demonstrating, he said, that “you can survive heat shock with the normal level of heat shock proteins, as long as you make your cytoskeleton work better.”

    He noted that the team’s results – that boosting chaperones is not essential to surviving heat stress – were so contradictory to current thinking that “I made my post-docs’ lives hell for three years” insisting on more experiments to rule out errors. Yet, when Dillin presented the results recently to members of the protein-folding community, he said the first reaction of many was, “That makes perfect sense.”

    Dillin’s colleagues include Milos S. Simic and Suzanne C. Wolff of UC Berkeley, Ana R. Grant of the University of Michigan in Ann Arbor, James J. Moresco and John R. Yates III of Scripps in La Jolla, Calif., and Gerard Manning of Genentech, South San Francisco, Calif. The work is funded by the Howard Hughes Medical Institute as well as by the National Institute of General Medical Sciences (8 P41 GM103533-17) and National Institute on Aging (R01AG027463-04) of the National Institutes of Health.

    See the full article here.

    Founded in the wake of the gold rush by leaders of the newly established 31st state, the University of California’s flagship campus at Berkeley has become one of the preeminent universities in the world. Its early guiding lights, charged with providing education (both “practical” and “classical”) for the state’s people, gradually established a distinguished faculty (with 22 Nobel laureates to date), a stellar research library, and more than 350 academic programs.

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