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  • richardmitnick 7:55 pm on March 15, 2014 Permalink | Reply
    Tags: , , , , Medicine   

    From Broolhaven Lab: “Particle Beam Cancer Therapy: The Promise and Challenges” 

    Brookhaven Lab

    March 3, 2014
    Karen McNulty Walsh

    Advances in accelerators built for fundamental physics research have inspired improved cancer treatment facilities. But will one of the most promising—a carbon ion treatment facility—be built in the U.S.? Participants at a symposium organized by Brookhaven Lab for the 2014 AAAS meeting explored the science and surrounding issues.

    Accelerator physicists are natural-born problem solvers, finding ever more powerful ways to generate and steer particle beams for research into the mysteries of physics, materials, and matter. And from the very beginning, this field born at the dawn of the atomic age has actively sought ways to apply advanced technologies to tackle more practical problems. At the top of the list—even in those early days— was taking aim at cancer, the second leading cause of death in the U.S. today, affecting one in two men and one in three women.

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    Participants in a symposium and press briefing exploring the latest advances and challenges in particle therapy for cancer at the 2014 AAAS meeting: Eric Colby (U.S. Department of Energy), Jim Deye (National Cancer Institute), Hak Choy (University of Texas Southwestern Medical Center), Kathryn Held (Harvard Medical School and Massachusetts General Hospital), Stephen Peggs (Brookhaven National Laboratory and Stony Brook University), and Ken Peach (Oxford University). (Credit: AAAS)

    Using beams of accelerated protons or heavier ions such as carbon, oncologists can deliver cell-killing energy to precisely targeted tumors—and do so without causing extensive damage to surrounding healthy tissue, eliminating the major drawback of conventional radiation therapy using x-rays.

    “This is cancer care aimed at curing cancer, not just treating it,” said Ken Peach, a physicist and professor at the Particle Therapy Cancer Research Institute at Oxford University.

    Peach was one of six participants in a symposium exploring the latest advances and challenges in this field—and a related press briefing attended by more than 30 science journalists—at the 2014 meeting of the American Association for the Advancement of Science in Chicago on February 16. The session, “Targeting Tumors: Ion Beam Accelerators Take Aim at Cancer,” was organized by the U.S. Department of Energy’s (DOE’s) Brookhaven National Laboratory, an active partner in an effort to build a prototype carbon-ion accelerator for medical research and therapy. Brookhaven Lab is also currently the only place in the U.S. where scientists can conduct fundamental radiobiological studies of how beams of ions heavier than protons, such as carbon ions, affect cells and DNA.

    “We could cure a very high percentage of tumors if we could give sufficiently high doses of radiation, but we can’t because of the damage to healthy tissue,” said radiation biologist Kathryn Held of Harvard Medical School and Massachusetts General Hospital during her presentation. “That’s the advantage of particles. We can tailor the dose to the tumor and limit the amount of damage in the critical surrounding normal tissues.”

    Yet despite the promise of this approach and the emergence of encouraging clinical results from carbon treatment facilities in Asia and Europe, there are currently no carbon therapy centers operating in the U.S.

    Participants in the Brookhaven-organized session agreed: That situation has to change—especially since the very idea of particle therapy was born in the U.S. Much of the initial radiation biology and clinical work was done at DOE’s Lawrence Berkeley National Laboratory, and U.S. physicists have been pioneers in the field. The session explored this rich history, the rationale and technology for proton and carbon-ion therapy, and how a U.S. carbon-ion treatment facility might be built.
    Something old, something new, and a lot of things borrowed

    The session kicked off with an introduction from moderator James Deye, program director for the Division of Cancer Treatment and Diagnosis within the Radiation Research Program of the National Cancer Institute. “We’ll hear about something old, something new, and a lot of things borrowed,” he said, suggesting that a “marriage” joining scientists from diverse disciplines might be the key to realizing the promise of particle therapy.

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    Brookhaven Lab accelerator physicist Stephen Peggs with magnet technology that could reduce the size of particle accelerators needed to steer heavy ion beams and deliver cell-killing energy to precisely targeted tumors while sparing surrounding healthy tissue.

    Stephen Peggs, an accelerator physicist at Brookhaven Lab and adjunct professor at Stony Brook University, recapped the birth of the idea of particle therapy and the field of accelerator science just after World War II—both coinciding with the formation of the U.S. national laboratories, now run by DOE.

    “When Harvard physicist Robert Wilson, who later became the first director of Fermilab [Fermi National Accelerator Laboratory], was asked to explore the potential dangers of proton particle radiation, he flipped the problem on its head and described how proton beams might be extremely useful—as effective killers of cancer cells,” he said.

    As Peggs explained, the reason is simple: Unlike conventional x-rays, which deposit energy—and cause damage—all along their path as they travel through healthy tissue en route to a tumor (and beyond it), protons and other ions deposit most of their energy where the beam stops. Using magnets, accelerators can steer these charged particles left, right, up, and down and vary the energy of the beam to precisely place the cell-killing energy right where it’s needed: in the tumor.

    The first implementation of particle therapy used helium and other ions generated by a machine built for fundamental physics research, the Bevatron accelerator at Berkeley Lab. Those pioneering spin-off studies “established a foundation for all subsequent ion therapy,” Peggs said. “It was also a ground-breaking and serendipitous demonstration of the transfer of emerging technology from DOE to medicine.”

    bevatron
    Edwin McMillan and Edward Lofgren on the shielding of the Bevatron. The shielding was only added later, after initial operations.

    As accelerators for physics research grew in size, pioneering experiments in particle therapy continued, operating “parasitically” at physics research facilities until the very first accelerator built for hospital-based proton therapy was completed with the help of DOE scientists at Fermilab in 1990. But even before that machine left Illinois for Loma Linda University Medical Center in California, said Peggs, who was at Fermilab at the time, physicists were thinking about how it could be made better. The mantra of making machines smaller, faster, cheaper—and capable of accelerating more kinds of ions—has driven the field since then.

    Advances in magnet technology, including compact superconducting magnets and beam-delivery systems developed at Brookhaven Lab, hold great promise for new machines. As a principal investigator in a Cooperative Research and Development Agreement (CRADA) contract between Brookhaven Lab and Best Medical International, Peggs is working to incorporate these technologies in a prototype ‘ion Rapid Cycling Medical Synchrotron’ (iRCMS) capable of delivering protons and/or carbon ions for radiobiology research and for treating patients.
    Small machine, big particle impact

    dna
    Different types of radiation treatment cause different kinds of damage to the DNA in a tumor cell. X-ray photons (top arrow) cause fairly simple damage (purple area) that cancer cells can sometimes repair between treatments. Charged particles—particularly ions heavier than protons (bottom arrow)—cause more and more complex forms of damage, resulting in less repair and a more lethal effect on the tumor. (Credit: NASA)

    The benefits of using charged particles heavier than protons (e.g., carbon ions) stem not only from their physical properties—they stop and deposit their energy over an even smaller and better targeted tumor volume than protons—but also a range of biological advantages they have over x-rays, as Kathryn Held elaborated in her talk.

    Compared with x-ray photons, “carbon ions are much more effective at killing tumor cells,” she said. “They put a huge hole through DNA compared to the small pinprick caused by x-rays, which causes clustered or complex DNA damage that is less accurately repaired between treatments—less repaired, period—and thus more lethal [to the tumor].”

    In addition, she said, many human tumors develop regions of hypoxia—low oxygen levels—because the tumor grows faster than the blood supply. “These hypoxic cells are resistant to radiation damage with x-ray photons, but there is less resistance when heavy ions are used,” she said.

    Held highlighted how important it will be to conduct further research to explore, for example, which heavy ions are best and how treatment fractions should be delivered. Studies suggest that use of a smaller number of very high dose fractions, called hypofractionation, might be more effective, which would be “an advantage economically and an advantage to patients…but we need more basic biological studies to really understand these effects,” she said.

    There are very few places to conduct this research, Held pointed out. One is a facility built by NASA at Brookhaven Lab to explore the effects of space radiation on cells and DNA. The goal of the NASA Space Radiation Laboratory (NSRL) is to fully understand risks and design protections for future astronauts. But much of the research is relevant to understanding the mechanisms and basic radiobiological responses that can apply to the treatment of cancer.

    Held conducts research at NSRL, which has been funded by NASA and more recently by NCI, but additional facilities and funding are needed for research specifically aimed at understanding the radiobiological effects of heavier ions for potential cancer therapies, she emphasized.
    Applying the technology and the biology to cancer patients

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    “When you can target the tumor and spare critical tissue you get fewer side effects,” said Hak Choy, chair in the Department of Radiation Oncology at the University of Texas Southwestern Medical Center. (Credit: UT Southwestern)

    After hearing the talks by Peggs and Held, Hak Choy, a radiation oncologist and chair in the Department of Radiation Oncology at the University of Texas Southwestern Medical Center, asked, “What does this mean to you and your family and friends? How do we apply this technology and the biology to cancer patients?”

    He presented compelling data on the benefits of particle therapy, including improved outcomes and reduced side effects when compared with conventional radiation, particularly for treating tumors in sensitive areas such as the brain and spine and in children.

    “When you can target the tumor and spare critical tissue you get fewer side effects,” he said. For example, when treating brain tumors with protons, doctors can spare the nerve going to the eye or the cochlea to preserve vision and hearing. Data also show that children with brain tumors treated with protons have better scores on math and spelling tests than children treated with x-rays, he said.

    Data from Japan and Europe suggest that carbon ions could be three or four times more biologically potent than protons, Choy said. He presented impressive survival statistics for certain types of cancers where carbon therapy surpassed protons, and was even better than surgery for one type of salivary gland cancer.

    “And carbon therapy is noninvasive,” Choy emphasized.

    In one study, it appeared carbon therapy combined with chemotherapy boosted the two-year survival rate to 54 percent for pancreatic cancer, one of the deadliest forms of the disease. That’s nearly double the survival rate for any other form of therapy.

    But all these data come from comparisons between different treatment centers where other variables might influence results. In order to make direct comparisons between different treatment methods, you need randomized clinical trials, Choy explained. To conduct such trials you need a comprehensive hospital-based facility, and the cost estimates for building one are around $200-300 million.

    That sounds very expensive, Choy said, until you consider that the U.S. spends about $125 billion a year on cancer therapies—much of it for chemotherapy drugs that have marginal success or that never even make their way into clinical use.
    Perspectives on who would pay

    To kick off the discussion that followed the presentations, Deye noted that NCI recently announced a funding opportunity to help establish a research agenda for a carbon therapy facility, should one be built in the U.S.

    “NCI doesn’t do construction, but we do research,” he said, noting that NCI might fund research if a facility is built, or possibly provide support for clinical trials at some of the existing facilities in Asia or Europe.

    Eric Colby, program manager for the Accelerator Stewardship program in DOE’s Office of High Energy Physics, says he joined DOE because he saw a lot of interest and tech transfer opportunities to make this kind of cancer treatment cheaper, better, and faster. “The goal of accelerator stewardship,” he said, “is to look at technologies developed over the years for basic physics research to see how they can be used in other fields—to transfer technologies from basic science to new practical uses.”

    As Ken Peach summed up, “There is technology available for carbon ion therapy today, there is strong radiobiological evidence for its effectiveness, and there is strong clinical evidence for its effectiveness, but there is a huge amount of work still to be done.

    “New clinical facilities are desperately needed worldwide and particularly in the U.S., which was a pioneering leader in this field and has, frankly, fallen behind.”
    Questions about money

    That statement ignited a lively question and answer session concerning who would pay for such a facility and how those who put up the money could get the needed return on their investment.

    Making a comparison with cancer drug development, NCI’s Deye said, “The government doesn’t fund late-stage drug development in this country. That’s funded by big pharma. Maybe we need a comparable industrial investment [to push this technology forward].”

    For determining how those investments would be repaid, DOE’s Colby said, “Having a first center in place to demonstrate a business model is very important.”

    As Peach pointed out, “If you amortize the cost over the lifetime of the machine the cost per patient is not all that much higher than for conventional therapy.”

    Since it may be extremely difficult to convince anyone to make the initial investment, a more realistic way to start may be to build the smaller prototype machine envisioned by the partnership between Brookhaven Lab and Best Medical.

    “With a prototype machine,” said Brookhaven’s Peggs, “we can test technologies, fix inevitable glitches, and reduce risks for future clinical facilities” while conducting the needed radiobiological and clinical research.

    Choy agreed that prototypes might be the place to start. “If the patients understand the potential benefits of this they will come knocking at the door,” he said. “The big question is to look at what is the optimal design. You don’t want to make the huge investment until you know. We have to build prototypes of different designs to figure that out.”

    “One of the really encouraging things,” said Peach, “is that there is this enormous will from the scientists across the different disciplines to try to increase the efficacy of this promising therapy and make it more widely available.”

    See the full article here.

    One of ten national laboratories overseen and primarily funded by the Office of Science of the U.S. Department of Energy (DOE), Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. The Laboratory’s almost 3,000 scientists, engineers, and support staff are joined each year by more than 5,000 visiting researchers from around the world.Brookhaven is operated and managed for DOE’s Office of Science by Brookhaven Science Associates, a limited-liability company founded by Stony Brook University, the largest academic user of Laboratory facilities, and Battelle, a nonprofit, applied science and technology organization.
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  • richardmitnick 3:49 pm on February 27, 2014 Permalink | Reply
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    From Princeton: “Tracking genes on the path to genetic treatment” 

    Princeton University

    February 27, 2014
    John Sullivan, Office of Engineering Communications

    Before doctors like Matthias Kretzler can begin using the results of molecular research to treat patients, they need science to find an effective way to match genes with the specific cells involved in disease. As Kretzler explains, finding that link would eventually let physicians create far more effective diagnostic tools and treatments.

    “Among many uses, it would allow us to develop cell-type targeted therapies,” said Kretzler, a University of Michigan professor of internal medicine and computational medicine and bioinformatics. He recently collaborated with Princeton University professor Olga Troyanskaya on a way to match genes to cells. “If you identify a [disease] that is in the liver or in the kidney, you could target those areas and not affect other parts of the body,” he said.

    Although scientists have decoded the human genome — the list of all the genes in human cells — they still have great difficulty determining the specific genes that are activated to make a kidney cell as opposed to a liver or heart cell.

    In theory, an easy way to link genes to cells would be to isolate a cell and test it. However, solid human tissue is so closely packed that even the finest surgical techniques cannot separate types of cells efficiently enough for analysis. A kidney biopsy, for example, produces a mix of several different types of cells that Kretzler dismisses as “kidney soup.”

    That is where computers come in. Troyanskaya and her postdoctoral fellow and graduate students at Princeton have developed a system that allows computers to “virtually dissect” a kidney in a way that surgery cannot. The machine uses data from an array of gene-activity measurements in patients’ kidney biopsies to separate cells mathematically and identify genes that are turned on in a specific cell type.

    kidney
    Princeton University and University of Michigan researchers have developed a system that allows computers to “virtually dissect” a kidney in a way that surgery cannot. The machine uses data from an array of gene-activity measurements in patients’ kidney biopsies to mathematically separate cells and identify genes that are turned on in a specific cell type. The researchers identified 136 genes involved in the creation of a critical kidney cell called a podocyte, tiny cells that serve as filters in the kidneys and are frequently involved in kidney disease. The above image is of podocytes taken with a scanning electron microscope. The overlaying curve and formula provide an artistic representation of the computational approach that can separate podocyte-specific genes from genes expressed in other kidney cells. (Micrograph image courtesy of Matthias Kretzler, University of Michigan; art courtesy of Ruth Dannenfelser, Princeton University)

    “We call it in-silico nano-dissection,” said Troyanskaya, a professor of computer science and the Lewis-Sigler Institute for Integrative Genomics. Using a large database of such gene-activity measurements to track genetic lineage allows scientists to refine their analysis through thousands of measurements, something that would be impossible with individual cell cultures, she said.

    The method has proven far faster and significantly more effective than current techniques. In findings published Nov. 3 in the journal Genome Research, researchers from Kretzler’s lab at Michigan and Troyanskaya’s at Princeton reported that they had identified 136 genes involved in the creation of a critical kidney cell called a podocyte. In decades of research, only 46 had been previously identified.

    “The potential for this is huge,” said Behzad Najafian, a University of Washington assistant professor of pathology who specializes in renal pathology. “I believe this novel technique, which is a significant improvement in cell lineage-specific gene-expression analysis, will not only help us understand the pathophysiology of kidney diseases better through biopsy studies, but also provides a strong tool for discovery or validation of cell-specific urine or plasma biomarkers.”

    The researchers focused on the glomerulus, an area of the kidney where the podocyte cells filter the waste from blood that will eventually leave the body as urine. One of the main reasons the researchers chose to track the podocytes is that the tiny cells are frequently involved in kidney disease. The researchers wanted to identify genes active in the podocytes and thus determine which genes cause the cell to be able to perform the podocyte’s filtering function, differentiating it from other cell types in the kidneys.

    It is not an easy job. Even a biopsy precise enough to sample only the glomerulus leaves doctors with a mix of four cell types including the podocyte. This “soup” yields activity measurements for tens of thousands of molecular markers, called RNA.

    “It’s a little more complicated than this, but you can think of RNA as the instructions that come from the DNA, and we need to identify which of these instructions are active in the podocytes” said Casey Greene, who worked on the project as a postdoctoral researcher with Troyanskaya and is now an assistant professor of genetics at Dartmouth College.

    Kretzler’s team in Michigan first obtained data from the biopsies of 452 patients, each containing RNA from roughly 20,000 genes. The more RNA found in the sample from a particular gene, the more active that gene.

    The problem was that there was no easy way to link the 20,000 RNA markers in the “soup” with the cells that they came from. The researchers’ task was to fit the pieces of this puzzle together and to trace connections between cells and their corresponding genes. They started with some knowledge: years of previous studies of people with hereditary kidney disease had identified 46 genes associated with podocytes.

    To begin making connections beyond those 46, the researchers organized the data as a giant matrix. “Each column is a patient. Each row is a gene, indicated by an RNA level,” Troyanskaya said. “The problem is which of these is specifically coming from the podocytes.”

    Troyanskaya, Kretzler and their collaborators took advantage of each patient’s sample being unique. Patients’ genetic backgrounds are different and their personal histories include many small perturbations — caused by inflammation, disease, medication and many other environmental differences — that can change which genes are turned on in their samples and to what extent. Those variations allowed Troyanskaya and her team to identify patterns in the behaviors of the 46 known genes and look for that pattern in the activities of the thousands of unknown ones.

    The team was able to identify 136 genes linked to the podocytes. Two of those genes have been shown experimentally to be able to cause kidney disease. The computer’s identification of genes linked to podocytes was verified by staining the cell samples with antibodies — each of which reacts to a specific protein constructed from the RNA instructions. The researchers found that the computer’s predictions were 65 percent accurate. The accuracy of the best existing method, which involves experimentally isolating the podocyte cells in mice and measuring their expression patterns, is only 23 percent.

    Troyanskaya said the goal is to train the computer to come up with a mathematical formula that identifies links between similar patterns and what distinguishes them from other, unrelated patterns. It is essentially the general type of approach that companies use to evaluate customers’ buying habits to suggest new movies or purchases. “The genes that we know are specifically active in podocytes — they are the movies that we like,” Troyanskaya said.

    Although the researchers used kidney cells, Troyanskaya said the program also will work with other cell types, including other solid tissues that cannot be experimentally micro-dissected in humans. The program is available free to researchers on Princeton’s website.

    “We are very excited about these results and applying this approach to a variety of cell types and disease settings,” Troyanskaya said.

    Besides Troyanskaya and Kretzler, the researchers involved in the work included: Casey Greene, who worked on the project as a postdoctoral researcher with Troyanskaya and is now an assistant professor of genetics at Dartmouth College; Young-suk Lee and Qian Zhu, graduate students in computer science and genomics at Princeton; Markus Bitzer, Felix Eichinger, Jeffrey Hodgin, Song Jiang, Viji Nair, Wenjun Ju, of the University of Michigan; Masami Kehata, Min Li, and Maria Pia Rastaldi of Fondazione IRCCS Ca’ Grande Ospedale Maggiore Policlinico, Milan, Italy; and Clemens Cohen of the University of Zurich.

    Support for the work was provided by the National Institutes of Health and the National Science Foundation. Troyanskaya is a senior fellow of the Canadian Institute for Advanced Research.

    See the full article here.

    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 9:26 am on February 11, 2014 Permalink | Reply
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    From Caltech: “Caltech-Developed Method for Delivering HIV-Fighting Antibodies Proven Even More Promising” 

    Caltech Logo
    Caltech

    02/09/2014
    Kimm Fesenmaier

    In 2011, biologists at the California Institute of Technology (Caltech) demonstrated a highly effective method for delivering HIV-fighting antibodies to mice—a treatment that protected the mice from infection by a laboratory strain of HIV delivered intravenously. Now the researchers, led by Nobel Laureate David Baltimore, have shown that the same procedure is just as effective against a strain of HIV found in the real world, even when transmitted across mucosal surfaces.

    dlon't know

    The findings, which appear in the February 9 advance online publication of the journal Nature Medicine, suggest that the delivery method might be effective in preventing vaginal transmission of HIV between humans.”The method that we developed has now been validated in the most natural possible setting in a mouse,” says Baltimore, president emeritus and the Robert Andrews Millikan Professor of Biology at Caltech. “This procedure is extremely effective against a naturally transmitted strain and by an intravaginal infection route, which is a model of how HIV is transmitted in most of the infections that occur in the world.”The new delivery method—called Vectored ImmunoProphylaxis, or VIP for short—is not exactly a vaccine. Vaccines introduce substances such as antigens into the body to try to get the immune system to mount an appropriate attack—to generate antibodies that can block an infection or T cells that can attack infected cells. In the case of VIP, a small, harmless virus is injected and delivers genes to the muscle tissue, instructing it to generate specific antibodies. The researchers emphasize that the work was done in mice and that the leap from mice to humans is large. The team is now working with the Vaccine Research Center at the National Institutes of Health to begin clinical evaluation.The study, “Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission,” was supported by the UCLA Center for AIDS Research, the National Institutes of Health, and the Caltech-UCLA Joint Center for Translational Medicine. Caltech biology researchers Alejandro B. Balazs, Yong Ouyang, Christin H. Hong, Joyce Chen, and Steven M. Nguyen also contributed to the study, as well as Dinesh S. Rao of the David Geffen School of Medicine at UCLA and Dong Sung An of the UCLA AIDS Institute.

    See the full article here.

    The California Institute of Technology (commonly referred to as Caltech) is a private research university located in Pasadena, California, United States. Caltech has six academic divisions with strong emphases on science and engineering. Its 124-acre (50 ha) primary campus is located approximately 11 mi (18 km) northeast of downtown Los Angeles. “The mission of the California Institute of Technology is to expand human knowledge and benefit society through research integrated with education. We investigate the most challenging, fundamental problems in science and technology in a singularly collegial, interdisciplinary atmosphere, while educating outstanding students to become creative members of society.”
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  • richardmitnick 6:19 pm on February 6, 2014 Permalink | Reply
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    From Berkeley Lab: “New Insight into an Emerging Genome-Editing Tool” 


    Berkeley Lab

    Berkeley Researchers Show Expanded Role for Guide RNA in Cas9 Interactions with DNA

    February 06, 2014
    Lynn Yarris (510) 486-5375 lcyarris@lbl.gov

    The potential is there for bacteria and other microbes to be genetically engineered to perform a cornucopia of valuable goods and services, from the production of safer, more effective medicines and clean, green, sustainable fuels, to the clean-up and restoration of our air, water and land. Cells from eukaryotic organisms can also be modified for research or to fight disease. To achieve these and other worthy goals, the ability to precisely edit the instructions contained within a target’s genome is a must. A powerful new tool for genome editing and gene regulation has emerged in the form of a family of enzymes known as Cas9, which plays a critical role in the bacterial immune system. Cas9 should become an even more valuable tool with the creation of the first detailed picture of its three-dimensional shape by researchers with the Lawrence Berkeley National Laboratory (Berkeley Lab) and the University of California (UC) Berkeley.

    dna
    The crystal structure of SpyCas9 features a nuclease domain lobe (red) and an alpha-helical lobe (gray) each with a nucleic acid binding cleft that becomes functionalized when Cas9 binds to guide RNA.

    binding
    Upon binding with guide RNA, the two structural lobes of Cas9 reorient so that the two nucleic acid binding clefts face each other, forming a central channel that interfaces with target DNA.

    Biochemist Jennifer Doudna and biophysicist Eva Nogales, both of whom hold appointments with Berkeley Lab, UC Berkeley, and the Howard Hughes Medical Institute (HHMI), led an international collaboration that used x-ray crystallography to produce 2.6 and 2.2 angstrom (Å) resolution crystal structure images of two major types of Cas9 enzymes. The collaboration then used single-particle electron microscopy to reveal how Cas9 partners with its guide RNA to interact with target DNA. The results point the way to the rational design of new and improved versions of Cas9 enzymes for basic research and genetic engineering.

    “The combination of x-ray protein crystallography and electron microscopy single-particle analysis showed us something that was not anticipated,” says Nogales. “The Cas9 protein, on its own, exists in an inactive state, but upon binding to the guide RNA, the Cas9 protein undergoes a radical change in its three-dimensional structure that enables it to engage with the target DNA.”

    “Because we now have high-resolution structures of the two major types of Cas9 proteins, we can start to see how this family of bacterial enzymes has evolved,” Doudna says. “We see that the two structures are quite different from each other outside of their catalytic domains, suggesting an interesting structural plasticity that could explain how Cas9 is able to use different kinds of guide RNAs. Also, the differences in the two structures suggest that it may be possible to engineer smaller Cas9 variants and still retain function, an important goal for some genome engineering applications.”

    two
    Eva Nogales (left) and Jennifer Doudna led a study that produced the first detailed look at the 3D structure of the Cas9 enzyme and how it partners with guide RNA. (Photo by Roy Kaltschmidt)

    Doudna and Nogales are the corresponding authors, along with Martin Jinek of the University of Zurich, of a paper in Science that describes this research. The paper is titled Structures of Cas9 endonucleases reveal RNA-mediated conformational activation. Co-authors are Fuguo Jiang, David Taylor, Samuel Sternberg, Emine Kaya, Enbo Ma, Carolin Anders, Michael Hauer, Kaihong Zhou, Steven Lin, Mattias Kaplan, Anthony Iavarone and Emmanuelle Charpentier.

    See the full article here.

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

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  • richardmitnick 5:01 pm on February 3, 2014 Permalink | Reply
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    From Berkeley Lab: “How a Shape-shifting DNA-repair Machine Fights Cancer” 


    Berkeley Lab

    February 03, 2014
    Dan Krotz 510-484-5956 dakrotz@lbl.gov

    Maybe you’ve seen the movies or played with toy Transformers, those shape-shifting machines that morph in response to whatever challenge they face. It turns out that DNA-repair machines in your cells use a similar approach to fight cancer and other diseases, according to research led by scientists from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab).

    mre
    One protein complex, two very different shapes and functions: In the top image, the scientists created an Mre11-Rad50 mutation that speeds up hydrolysis, yielding an open state that favors a high-fidelity way to repair DNA. In the bottom image, the scientists slowed down hydrolysis, resulting in a closed ATP-bound state that favors low-fidelity DNA repair. (Credit: Tainer lab)

    As reported in a pair of new studies, the scientists gained new insights into how a protein complex called Mre11-Rad50 reshapes itself to take on different DNA-repair tasks.

    Their research sheds light on how this molecular restructuring leads to different outcomes in a cell. It could also guide the development of better cancer-fighting therapies and more effective gene therapies.

    As reported in a pair of new studies, the scientists gained new insights into how a protein complex called Mre11-Rad50 reshapes itself to take on different DNA-repair tasks.

    Their research sheds light on how this molecular restructuring leads to different outcomes in a cell. It could also guide the development of better cancer-fighting therapies and more effective gene therapies.

    Mre11-Rad50’s job is the same in your cells, your pet’s cells, or any organism’s. It detects and helps fix the gravest kind of DNA breaks in which both strands of a DNA double helix are cut. The protein complex binds to the broken DNA ends, sends out a signal that stops the cell from dividing, and uses its shape-shifting ability to choose which DNA repair process is launched to fix the broken DNA. If unrepaired, double strand breaks are lethal to the cell. In addition, a repair job gone wrong can lead to the proliferation of cancer cells.

    Little is known about how the protein’s Transformer-like capabilities relate to its DNA-repair functions, however.

    To learn more, the scientists modified the protein complex in ways that were designed to affect just one of the many activities it undertakes. They then used structural biology, biochemistry, and genomic tools to study the impacts of these modifications.

    “By targeting a single activity, we can make the protein complex go down a different pathway and learn how its dynamic structure changes,” says John Tainer of Berkeley Lab’s Life Sciences Division. He conducted the research with fellow Berkeley Lab scientist Gareth Williams and scientists from several other institutions.

    Adds Williams, “In some cases, we sped up or slowed down the protein complex’s movements, and by doing so we changed its biological outcomes.”

    sybll
    Much of the research was conducted at the SIBYLS beamline at the Advanced Light Source. SIBYLS stands for Structurally Integrated Biology for Life Sciences.

    Much of the research was conducted at the Advanced Light Source (ALS), a synchrotron located at Berkeley Lab that generates intense X-rays to probe the fundamental properties of substances. They used an ALS beamline called SYBILS, which combines X-ray scattering with X-ray diffraction capabilities. It yields atomic-resolution images of the crystal structures of proteins. It can also watch the transformation of the protein as it undergoes conformational changes.

    In one study published in the journal Molecular Cell, the scientists studied Mre11 from microbial cells. They developed two molecular inhibitors that block Mre11’s ability to cut DNA, a critical initial step in the repair process.

    They tested the effect of these inhibitors in human cells. They found that Mre11 first makes a nick away from the broken DNA strand it is repairing. Mre11 then works back toward the broken end. Previously, scientists thought that Mre11 always starts at the broken DNA end. They also found that when Mre11 cuts in the middle of a DNA strand, it initiates a high-precision DNA-repair pathway called homologous recombination repair.

    In another study published in EMBO Journal, the scientists created Rad50 mutations that either promote or destabilize the shape formed when the Rad50 subunit binds with ATP, a chemical that fuels the protein complex’s movements.

    Biochemical and functional assays conducted by Tanya Paull of the University of Texas at Austin revealed how these changes affect microbial, yeast, and human Mre11-Rad50 activities. Paul Russell at the Scripps Research Institute helped the scientists learn how these Rad50 mutations affect yeast cells.

    They found that some mutations slowed down ATP hydrolysis, which is how Rad50 and other enzymes use ATP as fuel. Other mutations sped it up. Both changes affected Mre11-Rad50’s workflow, and its biological outcomes, in a big way.

    “When we slowed down hydrolysis and favored the ATP-bound state, Rad50 favored a non-homologous end joining pathway, which is a low-fidelity way to repair DNA,” says Williams. “When we sped it up, the subunit favored homologous repair, which is the high-fidelity pathway.”

    This approach, in which scientists start with a specific protein mechanism and learn how it affects the entire organism, will help researchers develop a predictive understanding of how Mre11-Rad50 works.

    “It’s a ‘bottom up’ way to study proteins such as Mre11-Rad50, and it could guide the development of better cancer therapies and other applications,” says Tainer.

    See the full article, with further material, here.

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

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  • richardmitnick 2:27 pm on January 28, 2014 Permalink | Reply
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    From U.C Berkeley: “Researchers open door to new HIV therapy” 

    UC Berkeley

    January 28, 2014
    Robert Sanders

    People infected with the Human Immunodeficiency Virus (HIV) can stave off the symptoms of AIDS thanks to drug cocktails that mainly target three enzymes produced by the virus, but resistant strains pop up periodically that threaten to thwart these drug combos.

    aids
    The AIDS virus enters immune cells by binding to CD4 receptors embedded in the membrane (parallel lines) of the cell. But once a virus enters the cell, it makes a protein, Nef, that binds to the protein complex underlying CD4, tagging it for the waste bin. Potential anti-HIV drugs would disable one of the proteins (colored blobs) to which Nef binds, interfering with HIV’s strategy for spreading through the body. Image by James Hurley, UC Berkeley.

    Researchers at the University of California, Berkeley, and the National Institutes of Health have instead focused on a fourth protein, Nef, that hijacks host proteins and is essential to HIV’s lethality. The researchers have captured a high-resolution snapshot of Nef bound with a main host protein, and discovered a portion of the host protein that will make a promising target for the next-generation of anti-HIV drugs. By blocking the part of a key host protein to which Nef binds, it may be possible to slow or stop HIV.

    “We have imaged the molecular details for the first time,” said structural biologist James H. Hurley, UC Berkeley professor of molecular and cell biology. “Having these details in hand puts us in striking distance of designing drugs to block the binding site and, in doing so, block HIV infectivity.”

    Hurley, cell biologist Juan Bonifacino of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health and their colleagues report their findings in a paper published today (Jan. 28) by the open-access, online journal eLife.

    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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  • richardmitnick 8:17 am on November 16, 2013 Permalink | Reply
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    From APS at Argonne Lab: “The Most Detailed Picture Yet of a Key AIDS Protein” 

    News from Argonne National Laboratory

    November 14, 2013
    No Writer Credit

    The first atomic-level structure of the tripartite HIV (human immunodeficiency virus) envelope protein—long considered one of the most difficult targets in structural biology and of great value for medical science—has been determined by scientists using data obtained at three synchrotron x-ray light sources including the U.S. Department of Energy (DOE) Office of Science’s Advanced Photon Source.

    hiv
    The structure of the human immunodeficiency virus envelope protein, shown here bound by broadly neutralizing antibodies against two distinct sites of vulnerability. (Courtesy of The Scripps Research Institute)

    The new findings provide the most detailed picture yet of the acquired immune deficiency syndrome (AIDS)-causing virus’s complex envelope, including sites that future vaccines will try to mimic to elicit a protective immune response.

    “Most of the prior structural studies of this envelope complex focused on individual subunits; but we’ve needed the structure of the full complex to properly define the sites of vulnerability that could be targeted, for example with a vaccine,” said Ian A. Wilson of The Scripps Research Institute (TSRI) and a senior author of the new research that included colleagues from TSRI; Weill Cornell Medical College; the Ragon Institute of MGH, MIT, and Harvard; and the Academic Medical Center (The Netherlands). The findings were published in two papers in Science Express, the early online edition of the journal Science, on October 31, 2013.

    See the full article here.

    Argonne is managed by UChicago Argonne, LLC for the U.S. Department of Energy’s Office of Science

    The Advanced Photon Source at Argonne National Laboratory is one of five national synchrotron radiation light sources supported by the U.S. Department of Energy’s Office of Science to carry out applied and basic research to understand, predict, and ultimately control matter and energy at the electronic, atomic, and molecular levels, provide the foundations for new energy technologies, and support DOE missions in energy, environment, and national security.

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  • richardmitnick 7:34 pm on November 13, 2013 Permalink | Reply
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    From Caltech: “New Department of Medical Engineering Added by the Caltech Division of Engineering and Applied Science “ 

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    Caltech

    11/13/2013

    Cynthia Eller

    Caltech’s Division of Engineering and Applied Science (EAS) has added a new department to its roster: the Department of Medical Engineering (MedE). MedE joins EAS’s existing departments of Aerospace; Applied Physics and Materials Science; Computing and Mathematical Sciences; Electrical Engineering; Environmental Science and Engineering; and Mechanical and Civil Engineering. Like these other departments, MedE pulls together faculty from a broad range of specialties, both within EAS and outside it, to create an interdisciplinary program that aims to aid collaboration and provide graduate education in a critical area of engineering that directly and positively impacts human health and well-being.

    device
    A handheld medical diagnostic test cartridge, as developed by Thomas G. Myers Professor of Electrical Engineering Ali HajimiriCredit: Lance Hayashida

    See the full article here.

    The California Institute of Technology (commonly referred to as Caltech) is a private research university located in Pasadena, California, United States. Caltech has six academic divisions with strong emphases on science and engineering. Its 124-acre (50 ha) primary campus is located approximately 11 mi (18 km) northeast of downtown Los Angeles. “The mission of the California Institute of Technology is to expand human knowledge and benefit society through research integrated with education. We investigate the most challenging, fundamental problems in science and technology in a singularly collegial, interdisciplinary atmosphere, while educating outstanding students to become creative members of society.”
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  • richardmitnick 7:06 am on September 6, 2013 Permalink | Reply
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    From Brookhaven Lab: “Molecular Structure Reveals How the Antibiotic Streptomycin Works” 

    Brookhaven Lab

    September 5, 2013
    Laura Mgrdichian

    Streptomycin was the first antibiotic developed to treat tuberculosis yet until recently, scientists did not completely understand how it works at the molecular level. They knew that streptomycin blocks a critical process, the synthesis of proteins by ribosomes leading to bacterial cell death, but certain details of the interaction remained undiscovered. At Brookhaven National Laboratory’s National Synchrotron Light Source, researchers have used x-ray crystallography to complete the picture.

    strep
    A) A ribbon diagram of the ribosome’s streptomycin binding site. B) A close-up of the rectangular area outlined in A. Streptomycin Is represented as yellow sHcks and spheres, helices are colored red, dark green, cyan, orange, and blue.

    See the full article here.

    One of ten national laboratories overseen and primarily funded by the Office of Science of the U.S. Department of Energy (DOE), Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. The Laboratory’s almost 3,000 scientists, engineers, and support staff are joined each year by more than 5,000 visiting researchers from around the world.Brookhaven is operated and managed for DOE’s Office of Science by Brookhaven Science Associates, a limited-liability company founded by Stony Brook University, the largest academic user of Laboratory facilities, and Battelle, a nonprofit, applied science and technology organization.
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  • richardmitnick 11:12 am on September 4, 2013 Permalink | Reply
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    From CERN: “CERN to produce radioisotopes for health” 

    CERN New Masthead

    4 Sep 2013
    Marina Giampietro

    A groundbreaking ceremony at CERN today marked the beginning of the construction of CERN MEDICIS, a research facility that will make radioisotopes for medical applications. The facility will use a proton beam at ISOLDE to produce the isotopes, which are first destined for hospitals and research centres in Switzerland, and will progressively extend to a larger network of laboratories in Europe and beyond.

    CERN ISOLDE New
    ISOLDE

    Radioactive isotopes are unstable nuclei. They present the same number of protons and a different number of neutrons when compared to the equivalent stable chemical element. In medicine they can be used to reveal the locations of specific molecules in living tissue.

    To produce radioisotopes CERN MEDICIS will use the primary proton beam at ISOLDE, the radioactive beam facility that for over 40 years has provided beams for around 300 experiments at CERN.

    At ISOLDE, physicists direct a high-energy-proton beam from the Proton-Synchrotron Booster at a target. The beam loses only 10% of its intensity and energy on hitting the target so the particles that pass through can still be used. For CERN-MEDICIS, a second target will be placed behind the first, and used to produce useful radioisotopes.

    An automated conveyor will then carry this second target to the CERN MEDICIS infrastructure, where the radioisotopes will be extracted. CERN’s Knowledge Transfer group covered the cost of the conveyor using money from the KT Fund, and is providing a dedicated technology-transfer officer specializing in life sciences. The radioactive shipping service in CERN’s Radio Protection unit together with the logistic services will handle transporting the radioisotopes to the medical facilities where they are needed.

    depict
    A proton beam, entering from the left, hits a target at the ISOLDE facility, producing a shower of scattered particles (Image: ISOLDE)

    “The first part of activities will be fully dedicated to the production and shipping of radioisotopes to the clinical and research centres in the region,” says Thierry Stora, the CERN engineer who leads the CERN MEDICIS project. So far the Geneva University Hospital (HUG), the Lausanne University Hospital (CHUV) and the Swiss Institute for Experimental Cancer Research (ISREC) of the Swiss Federal Institute of Technology in Lausanne (EPFL) will use CERN’s isotopes. But there is room for expansion.

    “More research and treatment facilities in the member states have already expressed their interest in collaborating with CERN,” says Stora. “Researchers from the biomedical field are keen to share the diverse technical expertise we have at CERN, which is required to produce radioisotopes.”

    See the full article here, with links to other material.

    Meet CERN in a variety of places:

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