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  • richardmitnick 11:12 am on July 17, 2017 Permalink | Reply
    Tags: , , , Synthetic DNA technology and high throughput screening permit large-scale testing of structural stability of multitudes of computationally designed proteins, U Washington   

    From U Washington: “Feedback from 1000s of designs could transform protein engineering” 

    U Washington

    University of Washington

    07.12.2017
    Leila Gray
    206.685.0381
    leilag@uw.edu

    1
    A model of a computationally designed mini-protein from a large-scale study to test structural stability. Institute for Protein Design.

    The stage is set for a new era of data-driven protein molecular engineering as advances in DNA synthesis technology merge with improvements in computational design of new proteins.

    This week’s Science reports the largest-scale testing of folding stability for computationally designed proteins, made possible by a new high-throughput approach.

    The scientists are from the UW Medicine Institute for Protein Design at the University of Washington in Seattle and the University of Toronto in Ontario.

    The lead author of the paper is Gabriel Rocklin, a postdoctoral fellow in biochemistry at the University of Washington School of Medicine. The senior authors are Cheryl Arrowsmith, of the Princess Margaret Cancer Center, the Structural Genomics Consortium and the Department of Medical Biophysics at the University of Toronto, and David Baker, UW professor of biochemistry and a Howard Hughes Medical Institute investigator.

    Proteins are biological workhorses. Researchers want to build new molecules, not found naturally, that can perform tasks in preventing or treating disease, in industrial applications, in energy production, and in environmental cleanups.

    “However, computationally designed proteins often fail to form the folded structures that they were designed to have when they are actually tested in the lab,” Rocklin said.

    In the latest study, the researchers tested more than 15,000 newly designed mini-proteins that do not exist in nature to see whether they form folded structures. Even major protein design studies in the past few years have generally examined only 50 to 100 designs.

    “We learned a huge amount at this new scale, but the taste has given us an even larger appetite,” said Rocklin. “We’re eager to test hundreds of thousands of designs in the next few years.”

    The most recent testing led to the design of 2,788 stable protein structures and could have many bioengineering and synthetic biology applications. Their small size may be advantageous for treating diseases when the drug needs to reach the inside of a cell.

    2
    Design model structures from a comprehensive mutational analysis of stability in natural and designed proteins. UW Institute for Protein Design.

    Proteins are made of amino acid chains with specific sequences, and natural protein sequences are encoded in cellular DNA. These chains fold into 3-dimensional conformations. The sequence of the amino acids in the chain guide where it will bend and twist, and how parts will interact to hold the structure together.

    For decades, researchers have studied these interactions by examining the structures of naturally occurring proteins. However, natural protein structures are typically large and complex, with thousands of interactions that collectively hold the protein in its folded shape. Measuring the contribution of each interaction becomes very difficult.

    The scientists addressed this problem by computationally designing their own, much simpler proteins. These simpler proteins made it easier to analyze the different types of interactions that hold all proteins in their folded structures.

    “Still, even simple proteins are so complicated that it was important to study thousands of them to learn why they fold,” Rocklin said. “This had been impossible until recently, due to the cost of DNA. Each designed protein requires its own customized piece of DNA so that it can be made inside a cell. This has limited previous studies to testing only tens of designs.”

    To encode their designs of short proteins in this project, the researchers used what is called DNA oligo library synthesis technology. It was originally developed for other laboratory protocols, such as large gene assembly. One of the companies that provided their DNA is CustomArray in Bothell, Wash. They also used DNA libraries made by Agilent in Santa Clara, Calif., and Twist Bioscience in San Francisco.

    By repeating the cycle of computation and experimental testing over several iterations, the researchers learned from their design failures and progressively improved their modeling. Their design success rate rose from 6 percent to 47 percent. They also produced stable proteins in shapes where all of their first designs failed.

    Their large set of stable and unstable mini-proteins enabled them to quantitatively analyze which protein features correlated with folding. They also compared the stability of their designed proteins to similarly sized, naturally occurring proteins.

    The most stable natural protein the researchers identified was a much-studied protein from the bacteria Bacillus stearothermophilus.

    3
    The researchers compared the stability of some of their designed proteins to a natural protein found in a bacteria that withstands the high temperatures of hot springs like those in Yellowstone. Alice C. Gray.

    This organism basks in high temperatures, like those in hot springs and ocean thermal vents. Most proteins lose their folded structures under such high temperature conditions. Organisms that thrive there have evolved highly stable proteins that stay folded even when hot.

    “A total of 774 designed proteins had higher stability scores than this most protease-resistant monomeric protein,” the researchers noted. Proteases are enzymes that break down proteins, and were essential tools the researchers used to measure stability for their thousands of proteins.

    The researchers predict that, as DNA synthesis technology continues to improve, high-throughput protein design will become possible for larger, more complex protein structures.

    “We are moving away from the old style of protein design, which was a mix of computer modeling, human intuition, and small bits of evidence about what worked before.” Rocklin said. “Protein designers were like master craftsmen who used their experience to hand-sculpt each piece in their workshop. Sometimes things worked, but when they failed it was hard to say why. Our new approach lets us collect an enormous amount of data on what makes proteins stable. This data can now drive the design process.”

    Their study was supported by the Howard Hughes Medical Institute and the Natural Sciences and Research Council of Canada. Rocklin is a Merck Fellow of the Life Sciences Research Foundation. Arrowsmith holds a Canadian Research Chair in Structural Genomics.

    This work was facilitated by the Hyak supercomputer at the University of Washington and by donations of computing time from Rosetta@home participants.

    Rosetta@home project, a project running on BOINC software from UC Berkeley

    Dr. David Baker, Baker Lab, U Washington

    4
    Hyak supercomputer at the University of Washington

    See the full article here .

    Please help promote STEM in your local schools.

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    u-washington-campus
    The University of Washington is one of the world’s preeminent public universities. Our impact on individuals, on our region, and on the world is profound — whether we are launching young people into a boundless future or confronting the grand challenges of our time through undaunted research and scholarship. Ranked number 10 in the world in Shanghai Jiao Tong University rankings and educating more than 54,000 students annually, our students and faculty work together to turn ideas into impact and in the process transform lives and our world. For more about our impact on the world, every day.
    So what defines us —the students, faculty and community members at the University of Washington? Above all, it’s our belief in possibility and our unshakable optimism. It’s a connection to others, both near and far. It’s a hunger that pushes us to tackle challenges and pursue progress. It’s the conviction that together we can create a world of good. Join us on the journey.

     
  • richardmitnick 8:09 am on July 12, 2017 Permalink | Reply
    Tags: , , Chemotherapy before breast cancer surgery might fuel metastasis, , STAT, U Washington   

    From STAT via U Washington: “Chemotherapy before breast cancer surgery might fuel metastasis” 

    U Washington

    University of Washington

    1

    STAT

    July 10, 2017
    Sharon Begley

    2
    A breast cancer tumor imaged with a technique that highlights aspects of its microenvironment. National Cancer Institute/Univ. of Chicago Comprehensive Cancer Center. National Cancer Institute/Univ. of Chicago Comprehensive Cancer Center.

    When breast cancer patients get chemotherapy before surgery to remove their tumor, it can make remaining malignant cells spread to distant sites, resulting in incurable metastatic cancer, scientists reported last week.

    The main goal of pre-operative (neoadjuvant) chemotherapy for breast cancer is to shrink tumors so women can have a lumpectomy rather than a more invasive mastectomy. It was therefore initially used only on large tumors after being introduced about 25 years ago. But as fewer and fewer women were diagnosed with large breast tumors, pre-op chemo began to be used in patients with smaller cancers, too, in the hope that it would extend survival.

    But pre-op chemo can, instead, promote metastasis, scientists concluded from experiments in lab mice and human tissue, published in Science Translational Medicine.

    When breast cancer patients get chemotherapy before surgery to remove their tumor, it can make remaining malignant cells spread to distant sites, resulting in incurable metastatic cancer, scientists reported last week.

    The main goal of pre-operative (neoadjuvant) chemotherapy for breast cancer is to shrink tumors so women can have a lumpectomy rather than a more invasive mastectomy. It was therefore initially used only on large tumors after being introduced about 25 years ago. But as fewer and fewer women were diagnosed with large breast tumors, pre-op chemo began to be used in patients with smaller cancers, too, in the hope that it would extend survival.

    But pre-op chemo can, instead, promote metastasis, scientists concluded from experiments in lab mice and human tissue, published in Science Translational Medicine.

    The reason is that standard pre-op chemotherapies for breast cancer — paclitaxel, doxorubicin, and cyclophosphamide — affect the body’s on-ramps to the highways of metastasis, said biologist John Condeelis of Albert Einstein College of Medicine, senior author of the new study.

    Called “tumor microenvironments of metastasis,” these on-ramps are sites on blood vessels that special immune cells flock to. If the immune cells hook up with a tumor cell, they usher it into a blood vessel like a Lyft picking up a passenger. Since blood vessels are the highways to distant organs, the result is metastasis, or the spread of cancer to far-flung sites.

    Depending on characteristics such as how many tumor cells, blood vessel cells, and immune cells are touching each other, the tumor microenvironment can nearly triple the chance that a common type of breast cancer (estrogen-receptor positive/HER2 negative) that has reached the lymph nodes will also metastasize, Condeelis and colleagues showed in a 2014 study [NCBI] of 3,760 patients. The discovery of how the tumor microenvironment can fuel metastasis by whisking cancer cells into blood vessels so impressed Dr. Francis Collins, director of the National Institutes of Health, that he featured it in his blog.

    The new study took the next logical step: Can the tumor microenvironment be altered so that it promotes or thwarts metastasis?

    To find out, Einstein’s George Karagiannis spent nearly three years experimenting with lab mice whose genetic mutations make them spontaneously develop breast cancer, as well as mice given human breast tumors. In both cases, paclitaxel changed the tumor microenvironments in three ways, all more conducive to metastasis: The microenvironment had more of the immune cells that carry cancer cells into blood vessels, it developed blood vessels that were more permeable to cancer cells, and the tumor cells became more mobile, practically bounding into those molecular Lyfts.

    As a result, the mice had twice as many cancer cells zipping through their bloodstream and in their lungs compared with mice not treated with paclitaxel. Two other neoadjuvants, doxorubicin and cyclophosphamide, also promoted metastasis by altering the tumor microenvironment. “This showed that the tumor microenvironment is the doorway to metastasis,” Condeelis said.

    The scientists also analyzed tissue from 20 breast cancer patients who had undergone pre-op chemo (12 weeks of paclitaxel and four of doxorubicin and cyclophosphamide). Compared to before the chemo, the tumor microenvironment after treatment was more conducive to metastasis in most patients. In five, it got more than five times worse. No patient’s microenvironment got less friendly to metastasis.

    Pre-op chemo “may have unwanted long-term consequences in some breast cancer patients,” the Einstein researchers wrote.

    That finding is “fascinating, powerful, and very important,” said Julio Aguirre-Ghiso, of Mount Sinai School of Medicine, an expert in metastasis who was not involved in the study. “It raises awareness that we might have to be smarter about how we use chemotherapy.”

    Dr. Julie Gralow, a medical oncologist at the University of Washington, said that if pre-op chemo promoted metastasis, that should have shown up in studies that compared it to post-op chemo, but for the most part it hasn’t. However, that could be because only tumor cells containing certain proteins that make them especially mobile are affected in this way. “This is an interesting study, to say the least,” Gralow said. “I am willing to keep my mind open to the possibility that there are some breast cancer patients in whom things get worse” with pre-op chemo.

    One reason to question the findings, however, is that if pre-op chemo promotes metastasis in some patients, that might be expected to have shown up in studies of the therapy. Overall, in fact, those studies show [JCO] that “neoadjuvant chemotherapy does not seem to improve overall survival,” as the authors of an editorial in the Journal of Clinical Oncology wrote.

    That’s not as bad as decreasing survival, of course. But Einstein’s Dr. Maja Oktay, a co-author of the new research, cautioned that the typical length of the studies — six or so years — is too short to assess the risk of metastasis, “which can take more than 20 years” to appear, she said. Such patients might never be flagged as having metastatic cancer, let alone having it linked to pre-op chemo decades earlier, said Aguirre-Ghiso.

    On a brighter note, not all breast cancer patients have the kind of tumor microenvironment in which pre-op chemo can promote metastasis. Whether they do or not can be determined by a simple lab test, but one that is not routinely done, Condeelis said.

    Serendipitously, an experimental compound called rebastinib, being developed by Deciphera Pharmaceuticals, seems to be able to block the on-ramp to the metastasis highway. In a study currently recruiting patient volunteers [Clinical Trials.gov], the Einstein scientists (who have no financial relationship with Deciphera) are studying whether rebastinib can improve outcomes in metastatic breast cancer.

    See the full article here .

    Please help promote STEM in your local schools.

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    Stem Education Coalition

    u-washington-campus
    The University of Washington is one of the world’s preeminent public universities. Our impact on individuals, on our region, and on the world is profound — whether we are launching young people into a boundless future or confronting the grand challenges of our time through undaunted research and scholarship. Ranked number 10 in the world in Shanghai Jiao Tong University rankings and educating more than 54,000 students annually, our students and faculty work together to turn ideas into impact and in the process transform lives and our world. For more about our impact on the world, every day.
    So what defines us —the students, faculty and community members at the University of Washington? Above all, it’s our belief in possibility and our unshakable optimism. It’s a connection to others, both near and far. It’s a hunger that pushes us to tackle challenges and pursue progress. It’s the conviction that together we can create a world of good. Join us on the journey.

     
  • richardmitnick 2:26 pm on July 8, 2017 Permalink | Reply
    Tags: , , , , , HeraldNet, LSST-Large Synoptic Survey Telescope, U Washington   

    From U Washington via Heraldnet: “UW scientists may save the Earth using computer algorithms” 

    U Washington

    University of Washington

    1

    HeraldNet

    Jun 29th, 2017
    Katherine Long

    1
    Andrew Connolly, left, director of DIRAC, a new institute for intensive survey astrophysics at the University of Washington, and Zeljko Ivezic, a professor of astronomy and a key player in the development of software for the LSST telescope in Chile, stand in the planetarium at the UW. They’re involved in a major project to create a map of all the asteroids in our solar system, and to figure out which ones might pose a danger to Earth. (Ellen M. Banner/The Seattle Times) [U Washington]

    Scientists at the University of Washington are writing computer algorithms that could one day save the world — and that’s no exaggeration.

    Working away in the university’s quiet Physics/Astronomy building, these scientists are teaching computers how to sift through massive amounts of data to identify asteroids on a collision course with Earth.

    Together with 60 colleagues at six other universities, the 20 UW scientists are part of a massive new data project to catalog space itself, using the largest digital camera ever made.

    Five years from now, a sky-scanning telescope under construction in Chile will begin photographing the night sky with a 3,200-megapixel camera. The telescope will have the power to peer into the solar system and beyond, and track things we have never been able to track before — including asteroids, the rubble left behind during the formation of the solar system.

    LSST


    LSST Camera, built at SLAC



    LSST telescope, currently under construction at Cerro Pachón Chile, a 2,682-meter-high mountain in Coquimbo Region, in northern Chile, alongside the existing Gemini South and Southern Astrophysical Research Telescopes.

    When it is up and running, the Large Synoptic Survey Telescope (LSST) will produce 20 terabytes of images every night, and will be able to photograph half the night sky every three days, said Andrew Connolly, one of the UW astronomers working on the project.

    It will replace the Sloan Digital Sky Survey, which dates back to 1998, and which was only able to cover one-eighth the sky over 10 years.

    SDSS Telescope at Apache Point Observatory, NM, USA

    The LSST’s mission is different from NASA’s Hubble Space Telescope, which sends back detailed photos of specific regions of space, but does not take vast surveys of everything in the sky.

    NASA/ESA Hubble Telescope

    The danger asteroids pose became clear in 2013, when more than 1,000 people were reportedly injured after a meteor exploded near the Russian town of Chelyabinsk. (Meteorites are closely related to asteroids.)

    And 66 million years ago, many scientists believe, an asteroid the size of a mountain smashed into Mexico’s Yucatán Peninsula, dramatically changing Earth’s environment and wiping out the dinosaurs.

    Scientists have already plotted the orbits of more than 700,000 known asteroids in the solar system, said Željko Ivezic, a UW astronomy professor and project scientist for LSST. The LSST will help astronomers identify an estimated 5 million more.

    That’s why teaching a computer to identify asteroids is such vital work.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    u-washington-campus
    The University of Washington is one of the world’s preeminent public universities. Our impact on individuals, on our region, and on the world is profound — whether we are launching young people into a boundless future or confronting the grand challenges of our time through undaunted research and scholarship. Ranked number 10 in the world in Shanghai Jiao Tong University rankings and educating more than 54,000 students annually, our students and faculty work together to turn ideas into impact and in the process transform lives and our world. For more about our impact on the world, every day.

    So what defines us — the students, faculty and community members at the University of Washington? Above all, it’s our belief in possibility and our unshakable optimism. It’s a connection to others, both near and far. It’s a hunger that pushes us to tackle challenges and pursue progress. It’s the conviction that together we can create a world of good. Join us on the journey.

     
  • richardmitnick 10:03 am on July 6, 2017 Permalink | Reply
    Tags: Allen Discovery Center for Cell Lineage Tracing, , , , The Paul G. Allen Frontiers Group, U Washington   

    From U Washington: “The Paul G. Allen Frontiers Group announces center to map cell lineages” 

    U Washington

    University of Washington

    07.05.2017
    Rob Piercy
    robp@alleninstitute.org
    206-548-8486

    $10 million grant will create an Allen Discover Center at UW Medicine to generate the first global maps of cell lineage in complex organisms.

    1
    An artist’s conception of cells dividing. A new Allen Discovery Center will trace cell lineages to better understand the development of living organisms. Wikimedia

    The Paul G. Allen Frontiers Group announced today the creation of an Allen Discovery Center for Cell Lineage Tracing at UW Medicine, to be directed by Jay Shendure, University of Washington School of Medicine professor of genome sciences, and co-directed by Michael Elowitz at the California Institute of Technology, with site director Alex Schier at Harvard University.

    The Allen Discovery Center will use newly developed technology to create global maps of development that reveal the relationships between the vast numbers of diverse cells that make up a single organism, with major impacts across developmental biology, neuroscience, cancer biology, regenerative medicine and other fields. The Center is funded at $10 million over four years, with the potential for $30 million over eight years.

    Scientists have been asking questions about the ancestry and lineage of cells for over a century, but tracing the relationships between generations of cells has faced significant technical challenges. In the past several years, teams led by Shendure at UW Medicine, Elowitz and Long Cai, at Caltech and Schier at Harvard have created new technologies that take advantage of modern gene editing methods to effectively trace cells as they divide, move and differentiate throughout an organism’s development.

    The Allen Discovery Center for Cell Lineage Tracing will use these new technologies and paradigms to develop lineage maps for the zebrafish and mouse – the first global maps of development in any vertebrate. They will also develop genomic systems to record the molecular events that regulate development. The Center’s other investigators are Carlos Lois at Caltech and Marshall Horwitz, professor of pathology, and Cole Trapnell, assistant professor of genome sciences, both at the UW School of Medicine.

    “For the first time, we have the tools and technology to answer questions that have fascinated developmental biologists for decades,” said Shendure. “By inserting ‘barcodes’ into the genome that mutate throughout development, we can essentially create a family tree for an organism’s cells, which tells us each cell’s relationships to its ancestors and other cells both near and far. We hope that the generation of technologies that we’re developing will enable us to gain the same kind of global view on development that the Human Genome Project provided for our genes.”

    “An amazing aspect of these technologies is that they should allow each cell to record its own individual molecular history within its own genome,” said Elowitz. “Reading out these cellular memoirs will provide new insights into development and disease.”

    “This application of genome editing and sequencing technologies will allow the study of development at unprecedented scales and create the new field of developmental statistics,” said Schier.

    “Each of us began as a single cell, which divided and specialized into the trillions of cells that make up an adult human,” said Tom Skalak, executive director of The Paul G. Allen Frontiers Group. “A fundamental scientific question is how this lineage of cells comes to be. This Allen Discovery Center is poised to produce solutions to this question, which would be transformative for many fields of bioscience.”

    “We expect this Allen Discovery Center to drive significant change in how we think about and study cell lineage, which is poised to have broad impact in biology,” said Ana Mari Cauce, University of Washington president. “We are glad for the support of The Paul G. Allen Frontiers Group and their recognition of the incredible work being led by our researchers.”

    “This collaborative work with scientists at Cal Tech, Harvard and UW Medicine will accelerate our knowledge of cell development in health and disease,” said Paul G. Ramsey, CEO of UW Medicine and dean of the UW School of Medicine. “We appreciate the partnership with The Paul G. Allen Frontiers Group and the commitment to advancing work in the biological sciences.

    Allen Discovery Centers are a new form of funding for leadership-driven, compass-guided research at the frontier of science. Having a comprehensive understanding of how an organism’s lineage map would have impact not just on the basic science of developmental biology, but also provide new insights into how cancer cells develop and how to manipulate development for regenerative medicine.

    About The Paul G. Allen Frontiers Group

    The Paul G. Allen Frontiers Group is dedicated to exploring the landscape of science to identify and fund pioneers with ideas that will advance knowledge and make the world better. Through continuous dialogue with scientists across the world, The Paul G. Allen Frontiers Group seeks opportunities to expand the boundaries of knowledge and solve important problems. Programs include the Allen Discovery Centers at partner institutions for leadership-driven, compass-guided research, and the Allen Distinguished Investigators for frontier explorations with exceptional creativity and potential impact. The Paul G. Allen Frontiers Group was founded in 2016 by philanthropist and visionary Paul G. Allen, and is a division of the Allen Institute, an independent 501(c)(3) medical research organization. For more information, visit allenfrontiersgroup.org.

    See the full article here .

    Please help promote STEM in your local schools.

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    u-washington-campus
    The University of Washington is one of the world’s preeminent public universities. Our impact on individuals, on our region, and on the world is profound — whether we are launching young people into a boundless future or confronting the grand challenges of our time through undaunted research and scholarship. Ranked number 10 in the world in Shanghai Jiao Tong University rankings and educating more than 54,000 students annually, our students and faculty work together to turn ideas into impact and in the process transform lives and our world. For more about our impact on the world, every day.
    So what defines us —the students, faculty and community members at the University of Washington? Above all, it’s our belief in possibility and our unshakable optimism. It’s a connection to others, both near and far. It’s a hunger that pushes us to tackle challenges and pursue progress. It’s the conviction that together we can create a world of good. Join us on the journey.

     
  • richardmitnick 9:31 am on July 6, 2017 Permalink | Reply
    Tags: , Battery free cell phone, U Washington   

    From U Washington: “First battery-free cellphone makes calls by harvesting ambient power” 

    U Washington

    University of Washington

    July 5, 2017
    Jennifer Langston

    1
    UW engineers have designed the first battery-free cellphone that can send and receive calls using only a few microwatts of power.Mark Stone/University of Washington

    University of Washington researchers have invented a cellphone that requires no batteries — a major leap forward in moving beyond chargers, cords and dying phones. Instead, the phone harvests the few microwatts of power it requires from either ambient radio signals or light.

    The team also made Skype calls using its battery-free phone, demonstrating that the prototype made of commercial, off-the-shelf components can receive and transmit speech and communicate with a base station.

    The new technology is detailed in a paper published July 1 in the Proceedings of the Association for Computing Machinery on Interactive, Mobile, Wearable and Ubiquitous Technologies [ACM-DL].

    “We’ve built what we believe is the first functioning cellphone that consumes almost zero power,” said co-author Shyam Gollakota, an associate professor in the Paul G. Allen School of Computer Science & Engineering at the UW. “To achieve the really, really low power consumption that you need to run a phone by harvesting energy from the environment, we had to fundamentally rethink how these devices are designed.”

    The team of UW computer scientists and electrical engineers eliminated a power-hungry step in most modern cellular transmissions — converting analog signals that convey sound into digital data that a phone can understand. This process consumes so much energy that it’s been impossible to design a phone that can rely on ambient power sources.

    Instead, the battery-free cellphone takes advantage of tiny vibrations in a phone’s microphone or speaker that occur when a person is talking into a phone or listening to a call.

    An antenna connected to those components converts that motion into changes in standard analog radio signal emitted by a cellular base station. This process essentially encodes speech patterns in reflected radio signals in a way that uses almost no power.

    To transmit speech, the phone uses vibrations from the device’s microphone to encode speech patterns in the reflected signals. To receive speech, it converts encoded radio signals into sound vibrations that that are picked up by the phone’s speaker. In the prototype device, the user presses a button to switch between these two “transmitting” and “listening” modes.

    2
    The battery-free phone developed at the UW can sense speech, actuate the earphones, and switch between uplink and downlink communications, all in real time. It is powered by either ambient radio signals or light.Mark Stone/University of Washington

    Using off-the-shelf components on a printed circuit board, the team demonstrated that the prototype can perform basic phone functions — transmitting speech and data and receiving user input via buttons. Using Skype, researchers were able to receive incoming calls, dial out and place callers on hold with the battery-free phone.

    “The cellphone is the device we depend on most today. So if there were one device you’d want to be able to use without batteries, it is the cellphone,” said faculty lead Joshua Smith, professor in both the Allen School and UW’s Department of Electrical Engineering. “The proof of concept we’ve developed is exciting today, and we think it could impact everyday devices in the future.”

    The team designed a custom base station to transmit and receive the radio signals. But that technology conceivably could be integrated into standard cellular network infrastructure or Wi-Fi routers now commonly used to make calls.

    “You could imagine in the future that all cell towers or Wi-Fi routers could come with our base station technology embedded in it,” said co-author Vamsi Talla, a former UW electrical engineering doctoral student and Allen School research associate. “And if every house has a Wi-Fi router in it, you could get battery-free cellphone coverage everywhere.”

    The battery-free phone does still require a small amount of energy to perform some operations. The prototype has a power budget of 3.5 microwatts.

    The UW researchers demonstrated how to harvest this small amount of energy from two different sources. The battery-free phone prototype can operate on power gathered from ambient radio signals transmitted by a base station up to 31 feet away.

    Using power harvested from ambient light with a tiny solar cell — roughly the size of a grain of rice — the device was able to communicate with a base station that was 50 feet away.

    3
    The research team from the UW Department of Electrical Engineering and the Allen School of Computer Science & Engineering includes (left to right): Vamsi Talla, Wu Meiling, Sam Crow, Joshua Smith, Bryce Kellogg and Shyam Gollakota.Mark Stone/University of Washington

    Many other battery-free technologies that rely on ambient energy sources, such as temperature sensors or an accelerometer, conserve power with intermittent operations. They take a reading and then “sleep” for a minute or two while they harvest enough energy to perform the next task. By contrast, a phone call requires the device to operate continuously for as long as the conversation lasts.

    “You can’t say hello and wait for a minute for the phone to go to sleep and harvest enough power to keep transmitting,” said co-author Bryce Kellogg, a UW electrical engineering doctoral student. “That’s been the biggest challenge — the amount of power you can actually gather from ambient radio or light is on the order of 1 or 10 microwatts. So real-time phone operations have been really hard to achieve without developing an entirely new approach to transmitting and receiving speech.”

    Next, the research team plans to focus on improving the battery-free phone’s operating range and encrypting conversations to make them secure. The team is also working to stream video over a battery-free cellphone and add a visual display feature to the phone using low-power E-ink screens.

    The research was funded by the National Science Foundation and Google Faculty Research Awards.

    For more information, visit batteryfreephone.cs.washington.edu or contact the research team at batteryfreephone@cs.washington.edu.

    See the full article here .

    Please help promote STEM in your local schools.

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    u-washington-campus
    The University of Washington is one of the world’s preeminent public universities. Our impact on individuals, on our region, and on the world is profound — whether we are launching young people into a boundless future or confronting the grand challenges of our time through undaunted research and scholarship. Ranked number 10 in the world in Shanghai Jiao Tong University rankings and educating more than 54,000 students annually, our students and faculty work together to turn ideas into impact and in the process transform lives and our world. For more about our impact on the world, every day.
    So what defines us —the students, faculty and community members at the University of Washington? Above all, it’s our belief in possibility and our unshakable optimism. It’s a connection to others, both near and far. It’s a hunger that pushes us to tackle challenges and pursue progress. It’s the conviction that together we can create a world of good. Join us on the journey.

     
  • richardmitnick 10:36 am on June 28, 2017 Permalink | Reply
    Tags: , , channelrhodopsin-2, , , , Purkinje cells, U Washington   

    From U Washington: “Study shines light on brain cells that control movement” 

    U Washington

    University of Washington

    06.26.2017
    Michael McCarthy
    Media contact:
    Leila Gray
    206.685.0381

    1
    In this image of neurons in the cerebellum of the brain, the yellow cells are Purkinje cells in which the channelrhodopsin-2 gene is being produced. Horwitz Lab/UW Medicine

    UW Medicine researchers have developed a technique for inserting a gene into specific cell types in the adult brain in an animal model.

    Recent work shows that the approach can be used to alter the function of brain circuits and change behavior. The study appears in the journal Neuron in the NeuroResources section.

    Gregory Horwitz, associate professor of physiology and biophysics at the University of Washington School of Medicine in Seattle, led the research team. He said that the approach will allow scientists to better understand what roles select cell types play in the brain’s complex circuitry.

    Researchers hope that the approach might someday lead to developing treatments for conditions, such as epilepsy, that might be curable by activating a small group of cells

    “The brain is made up of a mix of many cell types performing different functions. One of the big challenges for neuroscience is finding ways to study the function of specific cell types selectively without affecting the function of other cell types nearby,” Horwitz said. “Our study shows it is possible to selectively target a specific cell type in an adult brain using this technique and affect behavior nearly instantly.”

    In their study, Horowitz and his colleagues at the Washington National Primate Research Center in Seattle inserted a gene into cells in the cerebellum, a small structure located at the back of the brain and tucked under the brain’s larger cerebrum.

    The cerebellum’s primary function is controlling motor movements. Disorders of the cerebellum generally lead to often disabling loss of coordination. Recent research suggests the cerebellum may also be important in learning and may be involved in such conditions as autism and schizophrenia.

    The cells the scientists selected to study are called Purkinje cells. These cells, named after their discoverer, Czech anatomist Jan Evangelista Purkinje, are some of the largest in the human brain. They typically make connections with hundreds of other brain cells.

    “The Purkinje cell is a mysterious cell,” said Horwitz. “It’s one of the biggest and most elaborate neurons and it processes signals from hundreds of thousands of other brain cells. We know it plays a critical role in movement and coordination. We just don’t know how.”

    The gene they inserted, called channelrhodopsin-2, encodes for a light-sensitive protein that inserts itself into the brain cell’s membrane. When exposed to light, it allows ions – tiny charged particles – to pass through the membrane. This triggers the brain cell to fire.

    The technique, called optogenetics, is commonly used to study brain function in mice. But in these studies, the gene must be introduced into the embryonic mouse cell.

    “This ‘transgenic’ approach has proved invaluable in the study of the brain,” Horwitz said. “But if we are someday going to use it to treat disease, we need to find a way to introduce the gene later in life, when most neurological disorders appear.”

    The challenge for his research team was how to introduce channelrhodopsin-2 into a specific cell type in an adult animal. To achieve this, they used a modified virus that carried the gene for channelrhodopsin-2 along with segment of DNA called a promoter. The promoter stimulates the cell to start expressing the gene and make the channelrhodopsin-2 membrane protein. To make sure the gene was expressed only by Purkinje cells, the researchers used a promoter that is strongly active in Purkinje cells, called L7/Pcp2.”

    In their paper, the researchers reported that by painlessly injecting the modified virus into a small area of the cerebellum of rhesus macaque monkeys, the channelrhodopsin-2 was taken up exclusively by the targeted Purkinje cells. The researchers then showed that when they exposed the treated cells to light through a fine optical fiber, they were able stimulate the cells to fire at different rates and affect the animals’ motor control.

    Horwitz said that it was the fact that Purkinje cells express L7/Pcp2 promoter at a higher rate than other cells that made them more likely to produce the channelrhodopsin-2 membrane protein.

    “This experiment demonstrates that you can engineer a viral vector with this specific promoter sequence and target a specific cell type,” he said. “The promoter is the magic. Next, we want to use other promoters to target other cell types involved in other types of behaviors.”

    Horwitz coauthors were: lead author Yasmine El-Shamayleh, a postdoctoral fellow; Yoshiko Kojima, an acting instructor; and Robijanto Soetedjo, a UW School of Medicine research associate professor of physiology and biophysics. All are researchers at the Washington National Primate Research Center.

    This study was funded by National Institutes of Health grants to the researchers; an NIH Office of Research Infrastructure Programs grant to the Washington National Primate Research Center, and a National Eye Institute Center Core Grant for Vision Research to the University of Washington School of Medicine.

    See the full article here .

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  • richardmitnick 12:44 pm on June 27, 2017 Permalink | Reply
    Tags: , Light-sheet microscope, , , U Washington   

    From U Washington: “Microscope can scan tumors during surgery and examine cancer biopsies in 3-D” 

    U Washington

    University of Washington

    June 26, 2017
    Jennifer Langston

    1
    A versatile light-sheet microscope developed at the University of Washington can provide surgeons with real-time pathology data to guide cancer-removal surgeries and can also non-destructively examine tumor biopsies in 3-D.Mark Stone/University of Washington

    When women undergo lumpectomies to remove breast cancer, doctors try to remove all the cancerous tissue while conserving as much of the healthy breast tissue as possible.

    But currently there’s no reliable way to determine during surgery whether the excised tissue is completely cancer-free at its margins — the proof that doctors need to be confident that they removed all of the tumor. It can take several days for pathologists using conventional methods to process and analyze the tissue.

    That’s why between 20 and 40 percent of women have to undergo second, third or even fourth breast-conserving surgeries to remove cancerous cells that were missed during the initial procedure, according to studies [JAMA].

    A new microscope invented by a team of University of Washington mechanical engineers and pathologists could help solve this, and other, problems. It can rapidly and non-destructively image the margins of large fresh tissue specimens with the same level of detail as traditional pathology — in no more than 30 minutes.

    “Surgeons are sort of flying blind during these breast-conserving surgeries,” said mechanical engineering professor Jonathan Liu. “Oftentimes they’ve left some tumor behind which they don’t know about until a few days later when the pathologist finds it.”

    “If we can rapidly image the entire surface or margin of the excised tissue during the procedure, we can tell them if they still have tumor left in the body or not. And that would be a huge benefit to cancer patients,” Liu said.

    The new light-sheet microscope — which is described in a new paper published June 26 in Nature Biomedical Engineering — offers other advantages over existing processes and microscope technologies. It conserves valuable tissue for genetic testing and diagnosis, quickly and accurately images the irregular surfaces of large clinical specimens, and allows pathologists to zoom in and “see” biopsy samples in three dimensions.

    “The tools we use in pathology have changed little over the past century,” said co-author Nicholas Reder, chief resident and clinical research fellow in UW Medicine’s Department of Pathology. “This light-sheet microscope represents a major advance for pathology and cancer patients, allowing us to examine tissue in minutes rather than days and to view it in three dimensions instead of two — which will ultimately lead to improved clinical care.”

    Current pathology techniques involve processing and staining tissue samples, embedding them in wax blocks, slicing them thinly, mounting them on slides, staining them, and then viewing these two-dimensional tissue sections with traditional microscopes — a process that can take days to yield results.

    Another technique to provide real-time information during surgeries involves freezing and slicing the tissue for quick viewing. But the quality of those images is inconsistent, and certain fatty tissues, such as those from the breast, do not freeze well enough to reliably use the technique.

    By contrast, the UW open-top light-sheet microscope uses a sheet of light to optically “slice” through and image a tissue sample without destroying any of it. All of the tissue is conserved for potential downstream molecular testing, which can yield additional valuable information about the nature of the cancer and lead to more effective treatment decisions.

    3
    This comparison shows images of breast tissue taken by the open-top light-sheet microscope (left), traditional pathology techniques (middle) and frozen sectioning during surgery (right). The first two images reveal crisp details of cellular and nuclear features, while the frozen-section image is distorted due to the challenges of freezing fatty breast tissues. While the formalin-fixed paraffin-embedded section requires hours of preparation, the light-sheet microscope image is captured in minutes.Glaser et al./ Nature Biomedical Engineering

    Slide-based pathology is still an analog technique, much like radiology was several decades ago when X-rays were obtained on film. By imaging tissues in 3-D without having to mount thin tissue sections on glass slides, we are trying to transform pathology much like 3-D X-ray CT has transformed radiology,” Liu said. “While it is possible to scan microscope slides for digital pathology, we digitally image the intact tissues and bypass the need to prepare slides, which is simpler, faster and potentially less expensive.”

    “If we can do this without consuming any tissue, so much the better,” said co-author Larry True, professor of pathology at UW Medicine. “We want to use that valuable tissue for purposes which are becoming ever more important for treating patients — such as sequencing the tumor cells and finding genetic abnormalities that we can target with specific drugs and other precision medicine techniques.”

    The light-sheet microscope also offers advantages over other non-destructive optical- sectioning microscopes on the market today, which process images slowly and have difficulty maintaining the optimal focus when dealing with clinical specimens, which always have microscopic surface irregularities.

    The UW microscope can both image large tissue surfaces at high resolution and stitch together thousands of two-dimensional images per second to quickly create a 3-D image of a surgical or biopsy specimen. That additional data could one day allow pathologists to more accurately and consistently diagnose and grade tumors.

    “Pathologists are currently very limited in how much they can look at on a glass slide,” said co-author Adam Glaser, a postdoctoral fellow in the UW Molecular Biophotonics Laboratory. “If we can give them three-dimensional data, we can give them more information to help improve the accuracy of a patient’s diagnosis.”

    The UW team achieved these improvements by configuring various optical technologies in new ways and optimizing them for clinical use. Their open-top arrangement, which places all of the optics underneath a glass plate, allows them to image larger tissues than other microscopes.

    The team is currently working on speeding up the optical-clearing process that allows light to penetrate biopsy samples more easily. Future areas of research include optimizing their 3-D immunostaining processes, as well as as continuing a collaboration formed during the UW eScience Institute’s Winter Incubator program with Dr. Ariel Rokem to develop algorithms that can process the vast amounts of 3-D pathology data that their system generates, with the ultimate goal of helping pathologists zero in on suspicious areas of tissue.

    The research was funded by the National Institutes of Health and the University of Washington.

    Additional co-authors include Ye Chen, Chengbo Yin, Linpeng Wei and Yu Wang of the UW Department of Mechanical Engineering and Erin F. McCarty of UW Medicine’s Department of Pathology.

    For more information on the light-sheet microscope, contact Jonathan Liu at jonliu@uw.edu. To reach Larry True or Nicholas Reder at UW Medicine, contact Leila Gray at 206-685-0381 or leilag@uw.edu.

    See the full article here .

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    So what defines us —the students, faculty and community members at the University of Washington? Above all, it’s our belief in possibility and our unshakable optimism. It’s a connection to others, both near and far. It’s a hunger that pushes us to tackle challenges and pursue progress. It’s the conviction that together we can create a world of good. Join us on the journey.

     
  • richardmitnick 7:28 am on June 22, 2017 Permalink | Reply
    Tags: , , U Washington, UW-led scientists ‘closing the gap’ on malaria in India   

    From U Washington: “UW-led scientists ‘closing the gap’ on malaria in India” 

    U Washington

    University of Washington

    June 20, 2017
    James Urton

    1
    Pradipsinh Rathod, left, and Laura Chery, right.Dennis Wise/University of Washington

    The National Institutes of Health has renewed a major grant that funds a University of Washington-led research center to understand malaria in India.

    The initiative — Malaria Evolution in South Asia, which was first funded in 2010 — is one of 10 NIH-supported International Centers of Excellence for Malaria Research, or ICEMRs. The National Institute of Allergy and Infectious Diseases announced that it would provide $9.3 million in funds to the South Asia ICEMR over the next seven years, beginning July 1, 2017.

    South Asia sits in the middle of the malaria corridor that cuts from Southeast Asia to Africa.

    “India is a country of critical importance for understanding the spread of virulent malaria globally,” said Pradipsinh K. Rathod, a UW professor of chemistry and the director of the Malaria Evolution in South Asia ICEMR. “While most deaths caused by drug-resistant strains of malaria have occurred in Africa, most drug-resistant parasites arise first in Asia.”

    2
    At a South Asia ICEMR community site in rural Assam, a health worker inspects a bed net during a community survey.P.K. Mohapatra

    Malaria in India remains underappreciated. The country has 1.3 billion people and more than 90 percent of the population live in areas where there is risk of malaria transmission. India had an estimated 13 million cases of malaria in 2015, according to the World Health Organization. Beyond that, the picture of malaria in India is one of diversity.

    “There is enormous variation in the prevalence of malaria around the country — variation in levels of immunity and variation in the species of mosquitoes that spread the disease,” said Laura Chery, the South Asia ICEMR’s associate director. “Most importantly, there is unexpectedly high genetic diversity in malaria parasites that are circulating in India.”

    In addition to researchers from the UW, the South Asia ICEMR also includes U.S. scientists from Harvard University, the Fred Hutchinson Cancer Research Center, the Center for Infectious Disease Research and Stanford University. But by far the largest contingent of researchers that make up the center’s efforts are the dozens of scientists, clinicians and field workers at sites across India.

    “We have formed wonderful, productive partnerships with hospitals, clinics, government agencies and community members,” said Chery. “Together, we have learned to do advanced science on the ground at clinically important sites.”

    3
    At a South Asia ICEMR community site in rural Assam, site manager Devojit Sarma fills out a case report form while field workers conduct a household interview and prepare to test for malaria.P.K. Mohapatra

    Through partnerships with local hospitals and research institutes, the center currently works out of six sites across India. The locations capture the diversity of this massive country: Four sites are in eastern and northeastern India, where malaria is endemic and cases can reach as high as 50 to 100 per 1,000 people. Two other sites are on the west coast, where the prevalence of malaria can be relatively low — fewer than 1 case per 1,000 people. But these sites include urban hospitals that attract and treat large numbers of malaria patients, including migrants from other parts of the country.

    “We believe that movement of people within the country can partly explain the complexity of malaria in India,” said Rathod. “However, we do not fully understand the basis for such variations.”

    At each site, staff enroll patients to obtain malaria parasite samples, as well as information on each patient’s health history. From on-site laboratories in India, center staff and partners pursue a number of research projects: analyzing parasite samples for signs of drug resistance, understanding the basis for variations in disease presentation, sequencing parasite genomes and determining their genetic relatedness to one another, and testing how well different mosquito species take up various malaria strains.

    In addition to setting up complex research infrastructure, in its first seven years the center has made some surprising conclusions about malaria in India. Parasites in India show more genetic diversity than parasites in the rest of the world combined, according to Rathod. As a consequence, some standard laboratory tests for drug resistance, developed elsewhere in the world, do not accurately predict whether Indian parasites will show drug resistance.

    4
    At the Goa Medical College & Hospital, a lab technician reads malaria slides in the central laboratory, which reads roughly 20,000 malaria slides per year.Laura Chery

    Drug resistance is a major concern in malaria. Chloroquine was once an effective drug to fight malaria. But a generation ago, malaria parasites began to evolve resistance to it, rendering it largely ineffective. Today, the drug artemisinin is considered the best treatment against malaria. But artemisinin-resistant strains of malaria already have been identified in Southeast Asia. The Indian government and the South Asia ICEMR are on the lookout for artemisinin resistance among patients in northeastern and eastern India. Beyond that, the South Asia ICEMR is looking for parasites that mutate at extraordinary rates, as seen in Southeast Asia.

    “By getting a clearer picture of malaria in India, we’re ‘closing the gap’ on how this complex parasite behaves globally,” Rathod said.

    For the 2017-2024 cycle, other South Asia ICEMR project leaders are Neena Valecha, director of the National Institute of Malaria Research in India, and Manoj Duraisingh at Harvard University. Additional U.S.-based senior contributors are Joseph Smith at the Center for Infectious Disease Research, Shripad Tuljapurkar at Stanford University and James Kublin and Holly Janes at the Fred Hutchinson Cancer Research Center. Additional India-based senior contributors are Anup Anvikar at National Institute of Malaria Research; Subrata Baidya at Agartala Government Medical College; D.R. Bhattacharrya and P.K. Mohapatra at Regional Medical Research Centre, NE Region; Edwin Gomes at Goa Medical College & Hospital; Sanjeeb Kakati at Assam Medical College; Ashwani Kumar at National Institute of Malaria Research, Goa Field Unit; Sanjib Mohanty and A.K. Singh at Ispat General Hospital; and Swati Patankar at Indian Institute of Technology Bombay.

    See the full article here .

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    So what defines us —the students, faculty and community members at the University of Washington? Above all, it’s our belief in possibility and our unshakable optimism. It’s a connection to others, both near and far. It’s a hunger that pushes us to tackle challenges and pursue progress. It’s the conviction that together we can create a world of good. Join us on the journey.

     
  • richardmitnick 7:40 am on May 30, 2017 Permalink | Reply
    Tags: , , U Washington, UW anthropologist: Why researchers should share computer code   

    From U Wash: “UW anthropologist: Why researchers should share computer code” 

    U Washington

    University of Washington

    May 25, 2017
    Kim Eckart

    For years, scientists have discussed whether and how to share data from painstaking research and costly experiments. Some are further along in their efforts toward “open science” than others: Fields such as astronomy and oceanography, for example, involve such expensive and large-scale equipment and logistical challenges to data collection that collaboration among institutions has become the norm.

    Meanwhile, a variety of academic journals, including several in the Nature Research family, are turning their attention to another aspect of the research process: computer programming code. Code is becoming increasingly important in research because scientists are often writing their own computer programs to interpret their data, rather than using commercial software packages. Some journals now include scientific data and code as part of the peer-review process.

    And now, with the May 25 online publication of a commentary [Nature Neuroscience] by Ben Marwick, University of Washington associate professor of anthropology, and 13 other colleagues at universities across the United States and Europe, there are conventions and tools that researchers can use to make code sharing easier and more efficient. The team’s paper advocating the sharing of code appears in Nature Neuroscience, while the journal in an editorial [Nature Neiroscience] announces a pilot project to ask future authors to make their code available for review.

    “What we’re missing is the convention of sharing code or the tools for turning data into useful discoveries or information,” Marwick said. “Researchers say it’s great to have the data available in a paper — increasingly raw data are available in supplementary files or specialized online repositories — but the code for performing the clever analyses in between the raw data and the published figures and tables are still inaccessible.”

    Other Nature Research journals, such as Nature Methods and Nature Biotechnology, provide for code review as part of the article evaluation process. Since 2014, the company has encouraged writers to make their code available upon request.

    The Nature Neuroscience pilot focuses on three elements: whether the code supporting an author’s main claims is publicly accessible; whether the code functions without mistakes; and whether it produces the results cited.

    “This is a commitment from a high-impact journal to raise software to the status of a regular research product, that it’s not just a tool that gets discarded along the way, or hidden on a researcher’s computer where no-one else can benefit from it,” Marwick said. “In the future, scientific disciplines will be shifting to a position where you need to share your code as well as your data. It will be easier to reproduce someone’s new discovery, and incorporate their discoveries into your own work.”

    Imagine this scenario, Marwick said: A neuroscientist is trying to find new ways to identify early-stage tumors using 3-D brain imagery. She comes up with an algorithm that can pick out specific pixel values in an image, which helps lead to early tumor detection. By sharing the computer code and its mathematical algorithm, the scientist could facilitate a breakthrough.

    The Nature Neuroscience paper resulted from a two-day workshop held in 2014 in the United Kingdom, to Marwick, an archaeologist, was invited because of his efforts in using code and promoting open science in archaeology. A Senior Data Science Fellow at the UW eScience Institute, Marwick is active in the institute’s Reproducibility and Open Science Group, which works on issues and practices around tools and practices to enhance data sharing, preservation and reproducibility.

    Bill Howe, associate director of the eScience Institute, said code sharing is part of the future. “Reproducibility is literally the definition of science, and as science moves from the lab to the computer, code sharing must be at the core of how we conduct research and train students.”

    An open science approach to sharing code is not without its critics, as well as scientists who raise legal and ethical questions about the repercussions. How do researchers get proper credit for the code they share? How should code be cited in the scholarly literature? How will it count toward tenure and promotion applications? How is sharing code compatible with patents and commercialization of software technology?

    Marwick, who specializes in prehistoric human evolutionary ecology in Southeast Asia and Australia, has been advocating for code-sharing and related open science initiatives in archaeology through the Society of American Archaeology.

    “I’m just trying to shift the needle in my discipline to a practice that benefits everyone — researchers and the public,” he said.

    See the full article here .

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    So what defines us —the students, faculty and community members at the University of Washington? Above all, it’s our belief in possibility and our unshakable optimism. It’s a connection to others, both near and far. It’s a hunger that pushes us to tackle challenges and pursue progress. It’s the conviction that together we can create a world of good. Join us on the journey.

     
  • richardmitnick 9:21 am on May 25, 2017 Permalink | Reply
    Tags: "Unleashing the Power of Synthetic Proteins, , , , , U Washington   

    From Nautilus: “Unleashing the Power of Synthetic Proteins” 

    Nautilus

    Nautilus

    March 2017
    David Baker, Baker Lab, U Washngton, BOINC Rosetta@home project



    Dr. David Baker


    Rosetta@home project



    The opportunities for the design of synthetic proteins are endless.

    Proteins are the workhorses of all living creatures, fulfilling the instructions of DNA. They occur in a wide variety of complex structures and carry out all the important functions in our body and in all living organisms—digesting food, building tissue, transporting oxygen through the bloodstream, dividing cells, firing neurons, and powering muscles. Remarkably, this versatility comes from different combinations, or sequences, of just 20 amino acid molecules. How these linear sequences fold up into complex structures is just now beginning to be well understood (see box).

    Even more remarkably, nature seems to have made use of only a tiny fraction of the potential protein structures available—and there are many. Therein lies an amazing set of opportunities to design novel proteins with unique structures: synthetic proteins that do not occur in nature, but are made from the same set of naturally-occurring amino acids. These synthetic proteins can be “manufactured” by harnessing the genetic machinery of living things, such as in bacteria given appropriate DNA that specify the desired amino acid sequence. The ability to create and explore such synthetic proteins with atomic level accuracy—which we have demonstrated—has the potential to unlock new areas of basic research and to create practical applications in a wide range of fields.

    The design process starts by envisioning a novel structure to solve a particular problem or accomplish a specific function, and then works backwards to identify possible amino acid sequences that can fold up to this structure. The Rosetta protein modelling and design software identifies the most likely candidates—those that fold to the lowest energy state for the desired structure. Those sequences then move from the computer to the lab, where the synthetic protein is created and tested—preferably in partnership with other research teams that bring domain expertise for the type of protein being created.

    At present no other advanced technology can beat the remarkable precision with which proteins carry out their unique and beautiful functions. The methods of protein design expand the reach of protein technology, because the possibilities to create new synthetic proteins are essentially unlimited. We illustrate that claim with some of the new proteins we have already developed using this design process, and with examples of the fundamental research challenges and areas of practical application that they exemplify:

    2
    This image shows a designed synthetic protein of a type known as a TIM-barrel. Naturally occurring TIM-barrel proteins are found in a majority of enzymes, the catalysts that facilitate biochemical reactions in our bodies, in part because the circular cup-like or barrel shape at their core provides an appropriate space for the reaction to occur. The synthetic protein shown here has an idealized TIM-barrel template or blueprint that can be customized with pockets and binding sites and catalytic agents specific to particular reactants; the eight helical arms of the protein enhance the reaction space. This process can be used to design whole new classes of enzymes that do not occur in nature. Illustration and protein design prepared by Possu Huang in David Baker’s laboratory, University of Washington.

    Catalysts for clean energy and medicine. Protein enzymes are the most efficient catalysts known, far more so than any synthesized by inorganic chemists. Part of that efficiency comes from their ability to accurately position key parts of the enzyme in relation to reacting molecules, providing an environment that accelerates a reaction or lowers the energy needed for it to occur. Exactly how this occurs remains a fundamental problem which more experience with synthetic proteins may help to resolve.

    Already we have produced synthetic enzymes that catalyze potentially useful new metabolic pathways. These include: reactions that take carbon dioxide from the atmosphere and convert it into organic molecules, such as fuels, more efficiently than any inorganic catalyst, potentially enabling a carbon-neutral source of fuels; and reactions that address unsolved medical problems, including a potential oral therapeutic drug for patients with celiac disease that breaks down gluten in the stomach and other synthetic proteins to neutralize toxic amyloids found in Alzheimer’s disease.

    We have also begun to understand how to design, de novo, scaffolds that are the basis for entire superfamilies of known enzymes (Fig. 1) and other proteins known to bind the smaller molecules involved in basic biochemistry. This has opened the door for potential methods to degrade pollutants or toxins that threaten food safety.

    New super-strong materials. A potentially very useful new class of materials is that formed by hybrids of organic and inorganic matter. One naturally occurring example is abalone shell, which is made up of a combination of calcium carbonate bonded with proteins that results in a uniquely tough material. Apparently, other proteins involved in the process of forming the shell change the way in which the inorganic material precipitates onto the binding protein and also help organize the overall structure of the material. Synthetic proteins could potentially duplicate this process and expand this class of materials. Another class of materials are analogous to spider silk—organic materials that are both very strong and yet biodegradable—for which synthetic proteins might be uniquely suited, although how these are formed is not yet understood. We have also made synthetic proteins that create an interlocking pattern to form a surface only one molecule thick, which suggest possibilities for new anti-corrosion films or novel organic solar cells.

    Targeted therapeutic delivery. Self-assembling protein materials make a wide variety of containers or external barriers for living things, from protein shells for viruses to the exterior wall of virtually all living cells. We have developed a way to design and build similar containers: very small cage-like structures—protein nanoparticles—that self-assemble from one or two synthetic protein building blocks (Fig. 2). We do this extremely precisely, with control at the atomic level. Current work focuses on building these protein nanoparticles to carry a desired cargo—a drug or other therapeutic—inside the cage, while also incorporating other proteins of interest on their surface. The surface protein is chosen to bind to a similar protein on target cells.

    These self-assembling particles are a completely new way of delivering drugs to cells in a targeted fashion, avoiding harmful effects elsewhere in the body. Other nanoparticles might be designed to penetrate the blood-brain barrier, in order to deliver drugs or other therapies for brain diseases. We have also generated methods to design proteins that disrupt protein-protein interactions and proteins that bind to small molecules for use in biosensing applications, such as identifying pathogens. More fundamentally, synthetic proteins may well provide the tools that enable improved targeting of drugs and other therapies, as well as an improved ability to bond therapeutic packages tightly to a target cell wall.

    5
    A tiny 20-sided protein nanoparticle that can deliver drugs or other therapies to specific cells in the body with minimal side effects. The nanoparticle self-assembles from two types of synthetic proteins. Illustration and protein design prepared by Jacob Bale in David Baker’s laboratory, University of Washington.

    Novel vaccines for viral diseases. In addition to drug delivery, self-assembling protein nanoparticles are a promising foundation for the design of vaccines. By displaying stabilized versions of viral proteins on the surfaces of designed nanoparticles, we hope to elicit strong and specific immune responses in cells to neutralize viruses like HIV and influenza. We are currently investigating the potential of these nanoparticles as vaccines against a number of viruses. The thermal stability of these designer vaccines should help eliminate the need for complicated cold chain storage systems, broadening global access to life saving vaccines and supporting goals for eradication of viral diseases. The ability to shape these designed vaccines with atomic level accuracy also enables a systematic study of how immune systems recognize and defend against pathogens. In turn, the findings will support development of tolerizing vaccines, which could train the immune system to stop attacking host tissues in autoimmune disease or over-reacting to allergens in asthma.

    New peptide medicines. Most approved drugs are either bulky proteins or small molecules. Naturally occurring peptides (amino acid compounds) that are constrained or stabilized so that they precisely complement their biological target are intermediate in size, and are among the most potent pharmacological compounds known. In effect, they have the advantages of both proteins and small molecule drugs. The antibiotic cyclosporine is a familiar example. Unfortunately such peptides are few in number.

    We have recently demonstrated a new computational design method that can generate two broad classes of peptides that have exceptional stability against heat or chemical degradation. These include peptides that can be genetically encoded (and can be produced by bacteria) as well as some that include amino acids that do not occur in nature. Such peptides are, in effect, scaffolds or design templates for creating whole new classes of peptide medicines.

    In addition, we have developed general methods for designing small and stable proteins that bind strongly to pathogenic proteins. One such designed protein binds the viral glycoprotein hemagglutinin, which is responsible for influenza entry into cells. These designed proteins protect infected mice in both a prophylactic and therapeutic manner and therefore are potentially very powerful anti-flu medicines. Similar methods are being applied to design therapeutic proteins against the Ebola virus and other targets that are relevant in cancer or autoimmune diseases. More fundamentally, synthetic proteins may be useful as test probes in working out the detailed molecular chemistry of the immune system.

    Protein logic systems. The brain is a very energy-efficient logic system based entirely on proteins. Might it be possible to build a logic system—a computer—from synthetic proteins that would self-assemble and be both cheaper and more efficient than silicon logic systems? Naturally occurring protein switches are well studied, but building synthetic switches remains an unsolved challenge. Quite apart from bio-technology applications, understanding protein logic systems may have more fundamental results, such as clarifying how our brains make decisions or initiate processes.

    The opportunities for the design of synthetic proteins are endless, with new research frontiers and a huge variety of practical applications to be explored. In effect, we have an emerging ability to design new molecules to solve specific problems—just as modern technology does outside the realm of biology. This could not be a more exciting time for protein design.

    Predicting Protein Structure

    If we were unable to predict the structure that results from a given sequence of amino acids, synthetic protein design would be an almost impossible task. There are 20 naturally-occurring amino acids, which can be linked in any order and can fold into an astronomical number of potential structures. Fortunately the structure prediction problem is now well on the way toward being solved by the Rosetta protein modeling software.

    The Rosetta tool evaluates possible structures, calculates their energy states, and identifies the lowest energy structure—usually, the one that occurs in a living organism. For smaller proteins, Rosetta predictions are already reasonably accurate. The power and accuracy of the Rosetta algorithms are steadily improving thanks to the work of a cooperative global network of several hundred protein scientists. New discoveries—such as identifying amino acid pairs that co-evolve in living systems and thus are likely to be co-located in protein structures—are also helping to improve prediction accuracy.

    Our research team has already revealed the structures for more than a thousand protein families, and we expect to be able to predict the structure for nearly any protein within a few years. This is an important achievement with direct significance for basic biology and biomedical science, since understanding structure leads to understanding the function of the myriad proteins found in the human body and in all living things. Moreover, predicting protein structure is also the critical enabling tool for designing novel, “synthetic” proteins that do not occur in nature.

    How to Create Synthetic Proteins that Solve Important Problems

    6
    A graduate student in the Baker lab and a researcher at the Institute for Protein Design discuss a bacterial culture (in the Petri dish) that is producing synthetic proteins. Source: Laboratory of David Baker, University of Washington.

    Now that it is possible to design a variety of new proteins from scratch, it is imperative to identify the most pressing problems that need to be solved, and focus on designing the types of proteins that are needed to address these problems. Protein design researchers need to collaborate with experts in a wide variety of fields to take our work from initial protein design to the next stages of development. As the examples above suggest, those partners should include experts in industrial scale catalysis, fundamental materials science and materials processing, biomedical therapeutics and diagnostics, immunology and vaccine design, and both neural systems and computer logic. The partnerships should be sustained over multiple years in order to prioritize the most important problems and test successive potential solutions.

    A funding level of $100M over five years would propel protein design to the forefront of biomedical research, supporting multiple and parallel collaborations with experts worldwide to arrive at breakthroughs in medicine, energy, and technology, while also furthering a basic understanding of biological processes. Current funding is unable to meet the demands of this rapidly growing field and does not allow for the design and production of new proteins at an appropriate scale for testing and ultimately production, distribution, and implementation. Private philanthropy could overcome this deficit and allow us to jump ahead to the next generation of proteins—and thus to use the full capacity of the amino acid legacy that evolution has provided us.

    My BOINC

    See the full article here .

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