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  • richardmitnick 8:16 am on April 16, 2015 Permalink | Reply
    Tags: , , , Medicine   

    From Harvard: “Faster, Cheaper Testing” 

    Harvard University

    Harvard University

    April 13, 2015

    By quantifying the number of tumor-marker-targeting microbeads bound to cells (lower images), the D3 system categorizes high- and low-risk cervical biopsy samples as accurately as traditional pathology (upper images). Image: Massachusetts General Hospital Center for Systems Biology

    A device developed by Harvard Medical School investigators at Massachusetts General Hospital may bring rapid, accurate molecular diagnosis of cancer and other diseases to locations lacking the latest medical technology.

    In their report appearing in PNAS Early Edition, the researchers describe a smartphone-based device that uses technology for making holograms to collect detailed microscopic images for digital analysis of the molecular composition of cells and tissues.

    “The global burden of cancer, limited access to prompt pathology services in many regions and emerging cell profiling technologies increase the need for low-cost, portable and rapid diagnostic approaches that can be delivered at the point of care,” said Cesar Castro, HMS instructor in medicine at Mass General and co-lead author of the report. “The emerging genomic and biological data for various cancers, which can be essential to choosing the most appropriate therapy, supports the need for molecular profiling strategies that are more accessible to providers, clinical investigators and patients. We believe the platform we have developed provides essential features at an extraordinary low cost.”

    The device—called the D3 (digital diffraction diagnosis) system—features an imaging module with a battery-powered LED light clipped onto a standard smartphone. It records high-resolution imaging data with its camera.

    With a much greater field of view than traditional microscopy, the D3 system is capable of recording data on more than 100,000 cells from a blood or tissue sample in a single image. The data can then be transmitted for analysis to a remote graphic-processing server via a secure, encrypted cloud service. The results can be rapidly returned to the point of care.

    For molecular analysis of tumors, a sample of blood or tissue is labeled with microbeads that bind to known cancer-related molecules; the sample is then loaded into the D3 imaging module. After the image is recorded and data transmitted to the server, the presence of specific molecules is detected by analyzing the diffraction patterns generated by the microbeads.

    The use of variously sized or coated beads may offer unique diffraction signatures to facilitate detection. A numerical algorithm developed by the research team for the D3 platform can distinguish cells from beads and analyze as much as 10 MB of data in less than nine-hundredths of a second.

    A pilot test of the system with cancer cell lines detected the presence of tumor proteins with an accuracy matching the current gold standard for molecular profiling. The larger field of view enabled simultaneous analysis of more than 100,000 cells at a time.

    The investigators then conducted analysis of cervical biopsy samples from 25 women with abnormal Pap smears—samples collected along with those used for clinical diagnosis—using microbeads tagged with antibodies against three published markers of cervical cancer.

    Based on the number of antibody-tagged microbeads binding to cells, D3 analysis promptly and reliably categorized biopsy samples as high-risk, low-risk or benign, with results matching conventional pathologic analysis.

    D3 analysis of fine-needle lymph node biopsy samples was accurately able to differentiate four patients whose lymphoma diagnosis was confirmed by conventional pathology from another four with benign lymph node enlargement. Along with protein analyses, the system was enhanced to successfully detect DNA—in this instance from human papillomavirus—with great sensitivity.

    In these pilot tests, results of the D3 assay were available in under an hour and at a cost of $1.80 per assay, a price that would be expected to drop with further refinement of the system.

    “We expect that the D3 platform will enhance the breadth and depth of cancer screening in a way that is feasible and sustainable for resource limited-settings,” said Ralph Weissleder, HMS Thrall Family Professor of Radiology at Mass General, director of the Mass General Center for Systems Biology and co-senior author of the paper. “By taking advantage of the increased penetration of mobile phone technology worldwide, the system should allow the prompt triaging of suspicious or high-risk cases. That could help to offset delays caused by limited pathology services in those regions and reduce the need for patients to return for follow-up care, which is often challenging for them.”

    In their further development of this technology, co-senior author Hakho Lee, HMS assistant professor of radiology at Mass General, noted, “The research team will investigate the D3 platform’s ability to analyze protein and DNA markers of other disease catalysts, including infectious agents and allergens, integrate the software with larger databases and conduct clinical studies in settings such as care-delivery sites in developing countries or rural settings and for home testing with seamless sharing of information with providers and/or clinical investigators.”

    Mass General has filed a patent application covering the D3 technology.

    “Compared with traditional analysis techniques, the D3 mobile platform generates robust biological data while being significantly more cost-conscious, operable by nonspecialist end users and well-suited to point-of-care settings,” said co-lead author Hyungsoon Im, HMS research fellow in radiology at Mass General. “We have field tested the wireless readouts in rural areas of northern New England without problems and believe this technology is poised to deliver fast, low-cost and accurate cancer and HPV diagnosis.”

    The study was supported by National Institutes of Health grants R01-HL113156, R01-EB010011, R01-EB00462605A1, T32CA79443 and K12CA087723-11A1; National Heart, Lung and Blood Institute contract HHSN268201000044C; and Department of Defense Ovarian Cancer Research Program Award W81XWH-14-1-0279.

    See the full article here.

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

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

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  • richardmitnick 12:06 pm on April 4, 2015 Permalink | Reply
    Tags: , , Medicine, Science Times   

    From Science Times: “Cure for Cancer: Cure-All Borrelidin Molecule Could Hold the Key to Cancer Treatment” 

    Science Times

    Science Times

    Apr 02, 2015
    Quinn Fucile


    Natural or traditional medicine usually isn’t the strongest option when combating a disease. However, studying traditional herbs and other natural products can be an excellent starting point for modern medicine. Sometimes the source isn’t so obvious though, as many of our antibiotics come from fungus, bacteria, and other microbes.

    What scientists are discovering is that these naturally occurring compounds can act more subtly than many of our older medications. Things like broad-spectrum antibiotics are quickly falling out of favor, because they encourage microbes to evolve immunity and interfere with our bodies beneficial microbes. But for every precision tool, nature also produces the occasional blunt instrument, as is the case with borrelidin.

    Borrelidin was originally isolated from a particular bacterial species, now a team from the Scripps Research Institute are taking a closer look. (via EurekaAlert) It’s of great interest because it’s a tRNA synthesis inhibitor. Transfer RNA is an essential structure in protein synthesis. When a protein is being synthesized, the ribosome translates the messenger RNA into an amino acid chain. It can do this because tRNA structures link amino acid building blocks with corresponding code in the messenger RNA.

    So interfering with the production of tRNA quickly interferes with proteins synthesis as a whole, eventually shutting down an organism. Previous work on borrelidin showed that it also specifically interfered with the development of new blood vessels in animals. This could have major implications for cancer research, as limiting blood vessel growth could cut off a tumor’s nutrient supply.

    Different compounds in the same class of inhibitors have already shown effective in some cases. One is already an approved topical treatment for bacterial skin infections, and another has been shown to be an active ingredient in traditional treatments for malarial fever. But what these researchers found indicates that borrelidin might be the strongest in the group.

    They tested on both cultured human cells and E. coli bacteria, to analyze its effects on both eukaryotic and prokaryotic organisms. In both cases, the compound bound to four active sites in the tRNA synthesis enzyme. What the researchers described as an inhibitory overkill, it shuts down the enzyme extremely effectively and has extremely broad applications.

    The hope is to analyze the structure and function further to develop compounds based on borrelidin. It’s broad-spectrum applicability means that it could lead to better antibiotics, cancer treatments, malaria treatments, and even antifungal medication. The fact that it hits multiple targets means that it may be very difficult for pathogens to adapt around.

    See the full article here.

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    The Science Hub For The Internet…

    Sciencetimes.com prides itself in providing a complete informational and content package for science enthusiasts in the web who aim to remain updated and well-informed regarding a wide array of topics of their interest.

    We provide credible news & info., in-depth reference material about diverse subjects that matter to everyone. We are a source for original and timely science and research information as well as breaking news in the various fields we represent.

  • richardmitnick 9:07 am on April 3, 2015 Permalink | Reply
    Tags: , , , Medicine   

    From AAAS: “Personalized cancer vaccines may fight tumors” 



    2 April 2015
    Jocelyn Kaiser

    An artist’s conception of a tumor surrounded by blood and lymphatic vessels. C. Bickel/Science

    Cancer treatments that harness the body’s immune system to wipe out tumors have begun paying off for some patients for whom all other therapies have failed. Now, a small clinical study has found support for a newcomer on the cancer immunotherapy front. Injected with a vaccine designed to match specific mutations in their tumors, three patients with advanced melanoma had a strong immune response and in two their tumors shrunk or stabilized, at least temporarily. Although the study was mainly meant to test safety, the results suggest it holds promise for stopping tumors from growing.

    “There’s a lot of excitement about this approach,” says oncologist and cancer immunologist Craig Slingluff of the University of Virginia in Charlottesville, who was not involved with the study.

    Vaccines for infectious diseases typically deliver into the body bits of protein or other material from a virus or bacterium that trigger the immune system to defend against the invading pathogen. With cancer, the similar idea is to vaccinate a patient with immune-stimulating molecules, known as antigens, found only on tumor cells, so that the person’s immune system ends up attacking the tumor. But cancer vaccines have a poor record of success. That’s because most of the tumor antigens tested also appear in small amounts on healthy cells, and the immune system has mechanisms that make it tolerate, or ignore, these familiar antigens.

    Scientists have their eye on a more promising kind of tumor antigen: those that result from the mutations that riddle a tumor’s DNA, thanks to the chaos cancer causes to a genome. Some of these mutations do not appear in genes that drive cancer growth, but instead code for novel peptides—short proteins—that may act as antigens on the surface of tumor cells. Because these so-called neoantigens are completely foreign to the body, they could in theory make a cancer vaccine.

    Devising a neoantigen cancer vaccine requires sequencing a lot of tumor DNA, which wasn’t feasible or affordable until recently. But now that DNA sequencing costs have dropped and speeds increased, researchers at Washington University in St. Louis have begun exploring neoantigen cancer vaccines for melanoma, a tumor in which the sun’s ultraviolet light that sparks cancer-causing mutations also creates hundreds of additional mutations that are likely to include many coding for neoantigens.

    Human immunologist Beatriz Carreno, trial leader Gerald Linette, and collaborators recently studied three melanoma patients who had surgery to remove their tumors, but who had cancer cells that had spread to their lymph nodes, making tumors likely to recur. The researchers sequenced the exome, or protein-coding DNA, of each patient’s original melanoma tumor and compared it with the exome of their other cells to identify dozens of mutations coding for newly created peptides that might act as neoantigens. (Not all peptides made by a cell get displayed on its surface.) They analyzed the possible neoantigens’ structures and did lab tests to predict which are actually made by the cell and get displayed on its surface, then homed in on those most likely to trigger an immune response. For each melanoma patient they chose seven neoantigens unique to that person’s tumor.

    After taking blood from each patient and harvesting from it immune sentinels called dendritic cells, the researchers then mixed each patient’s set of neoantigens with these white blood cells so that they would display the peptides to other immune cells. The team used the neoantigen-coated dendritic cells to make personalized neoantigen vaccines that were infused into the patients three times over about 4 months.

    Carreno and collaborators found that a key measure of vaccine response, the number of immune system T cells specific to the neoantigens in each patient, rose in the patients’ blood, along with an increase in the diversity of these T cells. These neoantigen-specific T cells could also kill cultured melanoma cells expressing the same neoantigens, the team reports online today in Science.

    In one patient, metastatic tumors in the woman’s lungs shrank, then regrew, but are now stable after 8 months; the second person’s tumor remnants have also been stable for 9 months. A third patient who had received an immunotherapy drug after surgery that put his cancer in remission remains cancer-free. However, the trial was designed primarily to confirm the safety of the vaccine and immune response, not to test its effectiveness, and because the patients received other treatments, it is not possible to say whether the vaccine helped: “I would be speculating if I said that the vaccine had any benefit to the patients,” Linette says.

    But the fact that the study found “a pretty high magnitude of immune response,” combined with recent reports that a different neoantigen vaccine can fight cancer in mice, suggests the idea is “promising,” Slingluff says.

    Such a vaccine, which should be less toxic than chemotherapy, might be used to prevent cancer from recurring after surgery. It might also be combined with other immunotherapy drugs known as checkpoint inhibitors that seem to work best for cancers such as lung and melanoma in which tumors have many mutations. “The high anticipation is whether the one-two punch with checkpoint inhibition would work,” says Roger Lo, a melanoma researcher at the University of California, Los Angeles.

    See the full article here.

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

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  • richardmitnick 7:12 pm on March 28, 2015 Permalink | Reply
    Tags: , Medicine,   

    From SN: “Clean-up gene gone awry can cause Lou Gehrig’s disease” 

    ScienceNews bloc


    March 24, 2015
    Kate Baggaley

    Mutations on a gene necessary for keeping cells clean can cause Lou Gehrig’s disease, scientists report online March 24 in Nature Neuroscience. The gene is one of many that have been connected to the condition.

    In amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease, nerve cells that control voluntary movement die, leading to paralysis. Scientists have previously identified mutations in 29 genes that are linked with ALS, but these genes account for less than one-third of all cases.

    To track down more genes, a team of European researchers looked at the protein-coding DNA of 252 ALS patients with a family history of the disease, as well as of 827 healthy people. The team discovered eight mutations on a gene called TBK1 that were associated with ALS.

    TBK1 normally codes for a protein that controls inflammation and cleans out damaged proteins from cells. “We do not know which of these two principle functions of TBK1 is the more relevant one” to ALS, says coauthor Jochen Weishaupt, a neurologist at Ulm University in Germany. In cells with one of the eight TBK1 mutations, the protein either is missing or lacks components that it needs to interact with other proteins, the researchers found.

    TBK1 mutations may explain 2 percent of ALS cases that run in families, which make up about 10 percent of all incidences of the disease, Weishaupt says.

    See the full article here.

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  • richardmitnick 1:52 pm on March 27, 2015 Permalink | Reply
    Tags: Albuquerque Journal, , , Medicine   

    From Albuquerque Journal via LANL: “LANL takes on deadly bugs” 

    LANL bloc

    LANL Sign
    Los Alamos National Laboratory


    March 27, 2015
    D’Val Westphal

    Team members who discovered a treatment for resistant infections are, from left, Aimee Newsham, Dixie State University student; Rico Del Sesto, Dixie State University professor; David Fox, Los Alamos National Laboratory; Andrew Koppisch, Northern Arizona University professor; and Mattie Jones, Dixie State University student. (Courtesy of David Fox)

    This column is for everyone who has ever had to deal with a horrible infection – from the Streptococcus sp. that rots teeth, to the Pseudomonas aeruginosa that attacks diabetic patients’ feet, to the Methicillin-resistant Staphylococcus aureus (MRSA, i.e. flesh-eating bacteria) that makes any original medical problem much worse. And it’s for everyone who ever will.

    Considering a surgeon recently told me MRSA is our generation’s staph, in that it’s everywhere and on everything, that could be everybody.

    Treating these infections, known in the scientific world as biofilms, is expensive, time consuming, sickening and often unsuccessful when it comes to killing them before they kill their host. That’s because while they are responsible for up to 80 percent of all bacterial infections, they have their own protection that makes them 50 to 1,000 times more resistant to antibiotics.

    And that’s why a discovery at Los Alamos National Laboratory – a treatment with what amounts to fancy water – is beyond exciting. It could be life-changing and life-saving.

    Full disclosure: My mother contracted a biofilm infection after having a back surgery and spent years unsuccessfully fighting it with stronger and stronger oral and intravenous antibiotics that ultimately caused a serious reaction of their own. The drugs simply could not penetrate the infection to kill it. Doctors finally decided to remove the hardware (and its virulent bacteria) rather than continue a fruitless and damaging battle.

    In David Fox’s world, my mother would have had an antibiotic delivered via ionized liquid that could penetrate her skin, the biofilm, and kill the bug.

    Fox is a staff scientist in LANL’s Bioscience Division. For several years he and a team of fellow chemists and microbiologists have been working with ionic liquids – known as molten salts. Originally their work was for forensic applications, like how to pull certain molecules out of fabrics. The team then figured out they could also use the ionic liquids to deliver molecules: like antibiotics to an until-then impenetrable bacteria.


    So these scientists – Fox, Tari Kern, Katherine Lovejoy, Rico Del Sesto (now at Dixie State University), Rashi Iyer, Amber Nagy, Andrew Goumas, Tarryn Miller and Andrew Koppisch (now at Northern Arizona University) – started working with the University of California-Santa Barbara on using their ionized water for transdermal drug delivery.

    Instead of infection treatments that range from irritating to painful – organic solvents, injections and debridement – the team focused on using 12 ionic liquids “generally recognized as safe” (GRAS in science-speak). They grew opportunistic gram negative bacteria, then added individual ionic liquids and incubated, then rinsed.

    And what they found was a greater than 99.9999 percent bacteria cell death, with some of the ionic liquids “more effective than a 10 percent bleach solution.”

    And that was before adding antibiotics.

    The team then moved on to ensuring the liquids with dissolved antibiotics could penetrate pig skin and the bacteria’s protective layer – and got equally stunning results. “Ninety-five and 98 percent reduction in cell viability” with one of the ionic liquids and that liquid plus an antibiotic.

    By comparison, antibiotics alone had a 20 percent kill rate.

    So why should someone who’s never had a cavity or a diabetic ulcer or a MRSA infection care? Fox points out the “economic burden of skin disease is over $100 billion.” That MRSA-type infections acquired in hospitals account for an estimated “$10 billion in extra patient costs and over 10,000 deaths per year.” That “wounds from infected surgical incisions account for over 1 million additional hospital days.” And that 10 to 20 percent of diabetic ulcers – a function of the Pseudomonas aeruginosa infection – require amputation.

    In other words, we are all paying for it, in terms of money, health and life.

    The discovery is now moving into clinical studies with live subjects – mice – Fox says, and if those go as well, on to human clinical trials. Funding for the years of required additional research could come from energy companies that want to extract high-energy density molecules like biofuels from an organism (the research’s first application), from corporations that could use it to more efficiently deliver their drugs to patients, and/or from the military that wants to protect/treat its soldiers.

    “Thousands of people die from, and billions is spent on treating, these secondary infections,” Fox says. The LANL team could be “providing a new weapon to combat flesh-eating bacteria and other microbes. We hope we have found a new silver bullet to treat these infections. We hope that’s where we’re at.”

    And so does everyone who has had, or will get, one of these very nasty infections.

    See the full article here.

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    Los Alamos National Laboratory’s mission is to solve national security challenges through scientific excellence.

    LANL Campus

    Los Alamos National Laboratory, a multidisciplinary research institution engaged in strategic science on behalf of national security, is operated by Los Alamos National Security, LLC, a team composed of Bechtel National, the University of California, The Babcock & Wilcox Company, and URS for the Department of Energy’s National Nuclear Security Administration.

    Los Alamos enhances national security by ensuring the safety and reliability of the U.S. nuclear stockpile, developing technologies to reduce threats from weapons of mass destruction, and solving problems related to energy, environment, infrastructure, health, and global security concerns.

    Operated by Los Alamos National Security, LLC for the U.S. Dept. of Energy’s NNSA

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  • richardmitnick 12:38 pm on March 27, 2015 Permalink | Reply
    Tags: , , Johns-Hopkins U, Medicine   

    From Hopkins: “New genetic variant that causes autism identified by Johns Hopkins-led team” 

    Johns Hopkins
    Johns Hopkins University

    Mar 25, 2015
    Shawna Williams

    Using a novel approach that focuses on rare families severely affected by autism, a Johns Hopkins-led team of researchers has identified a new genetic cause of the disease.

    The rare genetic variant offers important insights into the root causes of autism, the researchers say. And, they suggest, their unconventional method can be used to identify other genetic causes of autism and other complex genetic conditions.

    A report on the study was published today in the journal Nature.

    In recent years, falling costs for genetic testing, together with powerful new means of storing and analyzing massive amounts of data, have ushered in the era of the genome-wide association and sequencing studies. These studies typically compare genetic sequencing data from thousands of people with and without a given disease to map the locations of genetic variants that contribute to the disease. While genome-wide association studies have linked many genes to particular diseases, their results have so far failed to lead to predictive genetic tests for common conditions, such as Alzheimer’s, autism, or schizophrenia.

    “In genetics, we all believe that you have to sequence endlessly before you can find anything,” says Aravinda Chakravarti, a professor in the Johns Hopkins University School of Medicine’s McKusick-Nathans Institute of Genetic Medicine. “I think whom you sequence is as important—if not more so—than how many people are sequenced.”

    With that idea, Chakravarti and his collaborators identified families in which more than one female has autism spectrum disorder, a condition first described at Johns Hopkins in 1943. For reasons that are not understood, girls are far less likely than boys to have autism. When girls do have the condition, however, their symptoms tend to be severe. Chakravarti reasoned that females with autism, particularly those with a close female relative who is also affected, must carry very potent genetic variants for the disease, and he wanted to find out what those were.

    The research team compared the gene sequences of autistic members of 13 such families to the gene sequences of people from a public database. They found four potential culprit genes and focused on one, called CTNND2, because it fell in a region of the genome known to be associated with another intellectual disability. When they studied the gene’s effects in zebrafish, mice, and cadaveric human brains, the research group found that the protein it makes affects how many other genes are regulated. The CTNND2 protein was found at far higher levels in fetal brains than in adult brains or other tissues, Chakravarti says, so it likely plays a key role in brain development.

    While autism-causing variants in CTNND2 are very rare, Chakravarti says, the finding provides a window into the general biology of autism.

    “To devise new therapies, we need to have a good understanding of how the disease comes about in the first place,” he says. “Genetics is a crucial way of doing that.”

    Chakravarti’s research group is now working to find the functions of the other three genes identified as possibly associated with autism. They plan to use the same principle to look for disease genes in future studies of 100 similar autism-affected families, as well as other illnesses.

    “We’ve shown that even for genetically complicated diseases, families that have an extreme presentation are very informative in identifying culprit genes and their functions—or, as geneticists are taught, ‘treasure your exceptions.'” Chakravarti says.

    Other authors on the paper are Tychele N. Turner, Kamal Sharma, Maria X. Sosa, Dallas R. Auer, Stephan J. Sanders, Daniel Moreno-De-Luca, Vasyl Pihur, Christa Lese Martin, Matthew W. State, and Richard Huganir of The Johns Hopkins University; Edwin C. Oh, Yangfan P. Liu, and Nicholas Katsanis of Duke University; Ryan L. Collins, Harrison Brand, and Michael E. Talkowski of Massachusetts General Hospital and Harvard Medical School; Teri Plona, Kristen Pike, and Daniel R. Soppet of Leidos Biomedical Research; Michael W. Smith of the National Human Genome Research Institute; SauWai Cheung of Baylor College of Medicine; and Edwin Cook of the University of Illinois at Chicago.

    This work was funded by grants from the Simons Foundation, the National Institute of Mental Health, and an Autism Speaks Dennis Weatherstone Predoctoral Fellowship.

    See the full article here.

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    Johns Hopkins Campus

    The Johns Hopkins University opened in 1876, with the inauguration of its first president, Daniel Coit Gilman. “What are we aiming at?” Gilman asked in his installation address. “The encouragement of research … and the advancement of individual scholars, who by their excellence will advance the sciences they pursue, and the society where they dwell.”

    The mission laid out by Gilman remains the university’s mission today, summed up in a simple but powerful restatement of Gilman’s own words: “Knowledge for the world.”

    What Gilman created was a research university, dedicated to advancing both students’ knowledge and the state of human knowledge through research and scholarship. Gilman believed that teaching and research are interdependent, that success in one depends on success in the other. A modern university, he believed, must do both well. The realization of Gilman’s philosophy at Johns Hopkins, and at other institutions that later attracted Johns Hopkins-trained scholars, revolutionized higher education in America, leading to the research university system as it exists today.

  • richardmitnick 7:23 am on March 27, 2015 Permalink | Reply
    Tags: , Medicine,   

    From Rockefeller: “Genetic mutation helps explain why, in rare cases, flu can kill” 

    Rockefeller U bloc

    Rockefeller University

    March 26, 2015
    Zach Veilleux | 212-327-8982

    A small number of children who catch the influenza virus fall so ill they end up in the hospital even while their family and friends recover easily. New research from Rockefeller helps explain why: a rare genetic mutation that prevents the production of a critical protein, interferon, that is needed to fight off the virus.

    Nobody likes getting the flu, but for some people, fluids and rest aren’t enough. A small number of children who catch the influenza virus fall so ill they end up in the hospital — perhaps needing ventilators to breathe — even while their family and friends recover easily. New research by Rockefeller University scientists, published March 26 in Science, helps explain why: a rare genetic mutation.

    The researchers scrutinized blood and tissue samples from a young girl who, at the age of two-and-a-half, developed acute respiratory distress syndrome after catching the flu, and ended up fighting for her life in the hospital. Years after her ordeal, which she survived, scientists led by Jean-Laurent Casanova discovered that it could be explained by a rare mutation she carries that prevented her from producing a protein, interferon, that helps fight off the virus.

    “This is the first example of a common, isolated and life-threatening infection of childhood that is shown to be also a genetic disease,” says Casanova. The good news from these results, however, is that clinicians have a new treatment option for children who mysteriously develop severe cases of the flu. “This finding suggests that one could treat severe flu of childhood with interferon, which is commercially available,” says Casanova, who is professor and head of the St. Giles Laboratory of Human Genetics of Infectious Disease at Rockefeller, as well as a Howard Hughes Medical Institute investigator.

    The fact that a child’s genes could affect the severity of her illness wasn’t a surprise to the members of Casanova’s lab, who have been studying this phenomenon for decades. For instance, they have discovered genetic differences that help explain why the herpes simplex virus — which causes innocuous cold sores in most people — can, in rare cases, lead to potentially fatal infections that spread to the brain.

    Turning their attention to influenza, Michael J. Ciancanelli, a research associate and senior member of Casanova’s lab, and his colleagues sequenced all genes in the genomes of the young girl who survived her dangerous bout of the flu and her parents, looking for mutations that might explain her vulnerability. Knowing how rare her reaction to the flu was, they narrowed their search to mutations that were unique to her, then focused only on those that affected the immune system.

    What emerged from their work was the finding that the girl had inherited two differently mutated copies of the gene IRF7, which encodes a protein that amplifies the production of interferon, a critical part of the body’s response to viral infections. “No other mutations could have explained her reaction to the influenza virus,” says Ciancanelli. “Each mutation is very uncommon and thus the likelihood of carrying two damaged copies of the gene is extremely rare.”

    Indeed, when they infected a sample of her blood cells that normally produce interferon —plasmacytoid dendritic cells — the researchers measured no interferon. In contrast, blood cells from her parents, who each carried only one mutated version of the gene, produced healthy amounts of interferon when exposed to influenza. “That really was definitive proof that a single, non-mutated copy of this gene is enough to allow people to mount a response to the virus,” says Ciancanelli.

    The researchers also employed a cutting-edge technology developed by their collaborators at Columbia University to reprogram the child’s skin cells into early progenitor cells, then differentiate those into lung cells, the front lines of influenza infections. Not surprisingly, the virus replicated more in the patient’s cells than in the same cells from healthy people.

    Although the patient remains susceptible to severe reactions to new influenza viruses, annual vaccination against seasonal flu has, so far, prevented the occurrence of severe symptoms, indiciating that IRF7 is not needed for adaptive immunity to secondary infection by a flu virus.

    Moreover, she hasn’t fallen nearly as ill from other viruses, suggesting her lack of IRF7-dependent interferon production may not leave her vulnerable to viruses overall — a situation the researchers say they have also noted with other mutations that underlie infectious disease.

    See the full article here.

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    Rockefeller U Campus

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

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

  • richardmitnick 2:47 pm on March 26, 2015 Permalink | Reply
    Tags: , , Medicine,   

    From Wisconsin: “Ebola whole virus vaccine shown effective, safe in primates” 

    U Wisconsin

    University of Wisconsin

    March 26, 2015
    Terry Devitt

    Ebola virus swarms the surface of a host cell in this electron micrograph. Like most viruses, Ebola requires the help of a host cell to survive and replicate. Photo: Takeshi Noda, University of Tokyo

    An Ebola whole virus vaccine, constructed using a novel experimental platform, has been shown to effectively protect monkeys exposed to the often fatal virus.

    The vaccine, described today (March 26, 2015) in the journal Science, was developed by a group led by Yoshihiro Kawaoka, a University of Wisconsin-Madison expert on avian influenza, Ebola and other viruses of medical importance. It differs from other Ebola vaccines because as an inactivated whole virus vaccine, it primes the host immune system with the full complement of Ebola viral proteins and genes, potentially conferring greater protection.

    “In terms of efficacy, this affords excellent protection,” explains Kawaoka, a professor of pathobiological sciences in the UW-Madison School of Veterinary Medicine and who also holds a faculty appointment at the University of Tokyo. “It is also a very safe vaccine.”

    The vaccine was constructed on an experimental platform first devised in 2008 by Peter Halfmann, a research scientist in Kawaoka’s lab. The system allows researchers to safely work with the virus thanks to the deletion of a key gene known as VP30, which the Ebola virus uses to make a protein required for it to reproduce in host cells. Ebola virus has only eight genes and, like most viruses, depends on the molecular machinery of host cells to grow and become infectious.

    By engineering monkey kidney cells to express the VP30 protein, the virus can be safely studied in the lab and be used as a basis for devising countermeasures like a whole virus vaccine. The vaccine reported by Kawaoka and his colleagues was additionally chemically inactivated using hydrogen peroxide, according to the new Science report.

    Ebola first emerged in 1976 in Sudan and Zaire. The current outbreak in West Africa has so far claimed more than 10,000 lives. There are no proven treatments or vaccines, although several vaccine platforms have been devised in recent years, four of which recently advanced to the clinical trial stage in humans.

    Yoshihiro Kawaoka

    The new vaccine reported by Kawaoka has not been tested in people. However, the successful tests in nonhuman primates conducted at the National Institutes of Health (NIH) Rocky Mountain Laboratories, a biosafety level 4 facility in Hamilton, Montana, may prompt further tests and possibly clinical trials of the new vaccine. The work at Rocky Mountain Laboratories was conducted in collaboration with a group led by Heinz Feldmann of NIH.

    Those studies were conducted with cynomolgus macaques, which are very susceptible to Ebola. “It’s the best model,” Kawaoka says. “If you get protection with this model, it’s working.”

    Ebola vaccines currently in trials include:

    A DNA-based plasmid vaccine that primes host cells with some of the Ebola proteins.
    A vaccine based on a replication incompetent chimpanzee respiratory virus engineered to express a key Ebola protein.
    A live attenuated virus from the same family of viruses that causes rabies, also engineered to express a critical Ebola protein.
    A vaccine based on a vaccinia virus and engineered to express a critical Ebola protein.

    Each of those strategies, Kawaoka notes, has drawbacks in terms of safety and delivery.

    Whole virus vaccines have long been used to successfully prevent serious human diseases, including polio, influenza, hepatitis and human papillomavirus-mediated cervical cancer.

    The advantage conferred by inactivated whole virus vaccines such as the one devised by Halfmann, Kawaoka and their colleagues is that they present the complete range of proteins and genetic material to the host immune system, which is then more likely to trigger a broader and more robust immune response.

    Early attempts to devise an inactivated whole virus Ebola vaccine through irradiation and the preservative formalin failed to protect monkeys exposed to the Ebola virus and were abandoned.

    Although the new vaccine has surpassed that hurdle, human trials are expensive and complex, costing millions of dollars.

    The Ebola vaccine study conducted by Kawaoka was supported by the National Institutes of Health and by the Japanese Health and Labour Sciences Research Grants.

    In addition to Kawaoka, co-authors of the new Science report include Halfmann, Lindsay Hill-Batorski and Gabriele Neumann of UW-Madison and Andrea Marzi, W. Lesley Shupert and Feldmann of the National Institute of Allergy and Infectious Diseases.

    See the full article here.

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    In achievement and prestige, the University of Wisconsin–Madison has long been recognized as one of America’s great universities. A public, land-grant institution, UW–Madison offers a complete spectrum of liberal arts studies, professional programs and student activities. Spanning 936 acres along the southern shore of Lake Mendota, the campus is located in the city of Madison.

  • richardmitnick 1:43 pm on March 25, 2015 Permalink | Reply
    Tags: , Medicine, ,   

    From NOVA: “Stems Cells Finally Deliver, But Not on Their Original Promise” 



    25 Mar 2015
    Carrie Arnold

    To scientists, stem cells represent the potential of the human body to heal itself. The cells are our body’s wide-eyed kindergarteners—they have the potential to do pretty much anything, from helping us obtain oxygen, digest food, or pump our blood. That flexibility has given scientists hope that they can coax stem cells to differentiate into and replace those damaged by illness.

    Almost immediately after scientists learned how to isolate stem cells from human embryos, the excitement was palpable. In the lab, they had already been coaxed into becoming heart muscle, bone marrow, and kidney cells. Entire companies were founded to translate therapies into clinical trials. Nearly 20 years on, though, only a handful of therapies using stem cells have been approved. Not quite the revolution we had envisioned back in 1998.

    But stem cells have delivered on another promise, one that is already having a broad impact on medical science. In their investigations into the potential therapeutic functions of stem cells, scientists have discovered another way to help those suffering from neurodegenerative and other incurable diseases. With stem cells, researchers can study how these diseases begin and even test the efficacy of drugs on cells from the very people they’re intended to treat.

    Getting to this point hasn’t been easy. Research into pluripotent stem cells, the most promising type, has faced a number of scientific and ethical hurdles. They were most readily found in developing embryos, but in 1995, Congress passed a bill that eliminated funding on embryonic stem cells. Since adult humans don’t have pluripotent stem cells, researchers were stuck.

    That changed in 2006, when Japanese scientist Shinya Yamanaka developed a way to create stem cells from a skin biopsy. Yamanaka’s process to create induced pluripotent stem cells (iPS cells) won him and his colleague John Gurdon a Nobel Prize in 2012. After years of setbacks, the stem cell revolution was back on.

    A cluster of iPS cells has been induced to express neural proteins, which have been tagged with fluorescent antibodies.

    Biomedical scientists in fields from cancer to heart disease have turned to iPS cells in their research. But the technique has been especially popular among scientists studying neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS) for two main reasons: One, since symptoms of these diseases don’t develop until rather late in the disease process, scientists haven’t had much knowledge about the early stages. IPS cells changed that by allowing scientists to study the very early stages of the disorder. And two, they provide novel ways of testing new drugs and potentially even personalizing treatment options.

    “It’s creating a sea change,” says Jeanne Loring, a stem cell biologist at the Scripps Research Institute in San Diego. “There will be tools available that have never been available before, and it will completely change drug development.”

    Beyond Animal Models

    Long before scientists knew that stem cells existed, they relied on animals to model diseases. Through careful breeding and, later, genetic engineering, researchers have developed rats, mice, fruit flies, roundworms, and other animals that display symptoms of the illness in question. Animal models remain useful, but they’re not perfect. While the biology of these animals often mimics humans’, they aren’t identical, and although some animals might share many of the overt symptoms of human illness, scientists can’t be sure that they experience the disease in the same way humans do.

    “Mouse models are useful research tools, but they rarely capture the disease process,” says Rick Livesey, a biologist at the University of Cambridge in the U.K. Many neurodegenerative diseases, like Alzheimer’s, he says, are perfect examples of the shortcomings of animal models. “No other species of animal actually gets Alzheimer’s disease, so any animal model is a compromise.”

    As a result, many drugs that seemed to be effective in animal models showed no benefit in humans. A study published in Alzheimer’s Research and Therapy in June 2014 estimated that 99.9% of Alzheimer’s clinical trials ended in failure, costing both money and lives. Scientists like Ole Isacson, a neuroscientist at Harvard University who studies Parkinson’s disease, were eager for a method that would let them investigate illnesses in a patient’s own cells, eliminating the need for expensive and imperfect animal models.

    Stem cells appeared to offer that potential, but when Congress banned federal funding in 1995 for research on embryos—and thus the development of new stem cell lines—scientists found their work had ground to a halt. As many researchers in the U.S. fretted over the future of stem cell research, scientists in Japan were developing a technique which would eliminate the need for embryonic stem cells. What’s more, it would allow researchers to create stem cells from the individuals who were suffering from the diseases they were studying.

    Cells in the body are able to specialize by turning on some sets of genes and switching off others. Every cell has a complete copy of the DNA, it’s just packed away in deep storage where the cell can’t easily access it. Yamanaka, the Nobel laureate, knew that finding the key to this storage locker and unpacking it could potentially turn any specialized cell back into a pluripotent stem cell. He focused in on a group of 24 genes that were active only in embryonic stem cells. If he could get adult, specialized cells to translate these genes into proteins, then they should revert to stem cells. Yamanaka settled on fibroblast cells as the source of iPS cells since these are easily obtained with a skin biopsy.

    Rather than trying to switch these genes back on, a difficult and time-consuming task, Yamanaka instead engineered a retrovirus to carry copies of these 24 genes to mouse fibroblast cells. Since many retroviruses insert their own genetic material into the genomes of the cells they infect, Yamanaka only had to deliver the virus once. All successive generations of cells inherited those 24 genes. Yamanaka first grew the fibroblasts in a dish, then infected them with his engineered retrovirus. Over repeated experiments, Yamanaka was able to narrow the suite of required genes from 24 down to just four.

    The process was far from perfect—it took several weeks to create the stem cells, and only around 0.01%–0.1% of the fibroblasts were actually converted to stem cells. But after Yamanaka published his results in Cell in 2006, scientists quickly began perfecting the procedure and developing other techniques. To say they have been successful would be an understatement. “The technology is so good now that I have the undergraduates in my lab doing the reprogramming,” Loring says.

    Accelerating Disease

    When he heard of Yamanaka’s discovery, Isacson, the Harvard neuroscientist studying Parkinson’s disease, had been using fetal neurons to try to replace diseased and dying neurons. Isacson realized “very quickly” that iPS cells could yield new discoveries about Parkinson’s. At the time, scientists were trying to determine exactly when the disease process started. It wasn’t easy. A person has to lose around 70% of their dopamine neurons before the first sign of movement disorder appears and Parkinson’s can be diagnosed. By that point, it’s too late to reverse that damage, a problem that is found in many if not all neurodegenerative diseases. Isacson wanted to know what was causing the neurons to die.

    Together with the National Institute of Neurological Disorders and Stroke consortium on iPS cells, Isacson obtained fibroblasts from patients with genetic mutations linked to Parkinson’s. Then, he reprogrammed these cells to become the specific type of neurons affected by Parkinson’s disease. “To our surprise, in the very strong hereditary forms of disease, we found that cells showed very strong signs of distress in the dish, even though they were newborn cells,” Isacson says.

    These experiments, published in Science Translational Medicine in 2012, showed that the disease process in Parkinson’s started far earlier than scientists expected. The distressed, differentiated neurons Isacson saw under the microscope were still just a few weeks old. People generally didn’t start showing symptoms for Parkinson’s disease until middle age or beyond.

    A clump of stem cells, seen here in green

    Isacson and his colleagues then tried to determine what was different between different cells with different mutations. The cells showed the most distress in their mitochondria, the parts of the cell that act as power plants by creating energy from oxygen and glucose. How that distress manifested, though, varied slightly depending on which mutation the patient carried. Neurons derived from an individual with a mutation in the LRRK2 gene consumed lower than expected amounts of oxygen, whereas the neurons derived from those carrying a mutation in PINK1 had much higher oxygen consumption. Neurons with these mutations were also more susceptible to a type of cellular damage known as oxidative stress.

    After exposing both groups of cells to a variety of environmental toxins, such as oligomycin and valinomycin, both of which affect mitochondria, Isacson and colleagues attempted to rescue the cells by using several compounds that had been found effective in animal models. Both the LRRK2 and the PINK1 cells responded well to the antioxidant coenzyme Q10, but had very different responses to the immunosuppressant drug rapamycin. Whereas LRRK2 showed beneficial responses to rapamycin, the PINK1 cells did not.

    To Isacson, the different responses were profoundly important. “Most drugs don’t become blockbusters because they don’t work for everyone. Trials start too late, and they don’t know the genetic background of the patient,” Isacson says. He believes that iPS cells will one day help researchers match specific treatments with specific genotypes. There may not be a single blockbuster that can treat Parkinson’s, but there may be several drugs that make meaningful differences in patients’ lives.

    Cancer biologists have already begun culturing tumor cells and testing anti-cancer drugs before giving these medications to patients, and biologists studying neurodegenerative disease hope that iPS cells will one day allow them to do something similar for their patients. Scientists studying ALS have recently taken a step in that direction, using iPS cells to create motor neurons from fibroblasts of people carrying a mutation in the C9orf72 gene, the most common genetic cause of ALS. In a recent paper in Neuron, the scientists identified a small molecule which blocked the formation of toxic proteins caused by this mutation in cultured motor neurons.

    Adding More Dimensions

    It’s one thing to identify early disease in iPS cells, but these cells are generally obtained from people who have been diagnosed. At that point, it’s too late, in a way; drugs may be much less likely to work in later stages of the disease. To make many potential drugs more effective, the disease has to be diagnosed much, much earlier. Recent work by Harvard University stem cell biologist Rudolph Tanzi and colleagues may have taken a step in that direction, also using iPS cells.

    Doo Yeon Kim, Tanzi’s co-author, had grown frustrated with iPS cell models of neurodegenerative disease. The cell cultures were liquid, and the cells could only grow in a thin, two-dimensional layer. The brain, however, was more gel-like, and existed in three dimensions. So Kim created a 3D gel matrix on which the researchers grew human neural stem cells that carried extra copies of two genes—one which codes for amyloid precursor protein and another for presenilin 1, both of which were previously discovered in Tanzi’s lab—which are linked to familial forms of Alzheimer’s disease.

    After six weeks, the cells contained high levels of the harmful beta-amyloid protein as well as large numbers of toxic neurofibrillary tangles that damage and kill neurons. Both of these proteins had been found at high levels in the neurons of individuals who had died from Alzheimer’s disease, but researchers didn’t know for certain which protein built up first and which was more central to the disease process. Further experiments revealed that drugs preventing the formation of amyloid proteins also prevented the formation of neurofibrillary tangles, indicating that amyloid proteins likely formed first during Alzheimer’s disease.

    “When you stop amyloid, you stop cell death,” Tanzi says. Amyloid begins to build up long before people show signs of altered cognition, and Tanzi believes that drugs which stop amyloid or prevent the buildup of neurofibrillary tangles could prevent Alzheimer’s before it starts.

    The results were hailed in the media as a “major breakthrough,” although Larry Goldstein, a neuroscientist at the University of California, San Diego, takes a more nuanced perspective. “It’s a nice paper and an important step forward, but things got overblown. I don’t know that I would use the word ‘breakthrough’ because these, like all results, often have a very long history to them,” Goldstein says.

    The scientists who spoke with NOVA Next about iPS cells noted that the field is moving forward at a remarkable clip, but they all talked at length about the issues that still remain. One of the largest revolves around differences between the age of the iPS cells and the age of the humans who develop these neurodegenerative diseases. Although scientists are working with neurons that are technically “mature,” they are nonetheless only weeks or months old—far from the several decades that the sufferers of neurodegenerative diseases have. Since aging remains the strongest risk factor for developing these diseases, neuroscientists worry that some disease pathology might be missed in such young cells. “Is it possible to study a disease that takes 70 years to develop in a person using cells that have grown for just a few months in a dish?” Livesey asks.

    So far, the answer has been a tentative yes. Some scientists have begun to devise different strategies to accelerate the aging process in the lab so researchers don’t have to wait several decades before they develop their answers. Lorenz Studer, director of the Center for Stem Cell Biology at the Sloan-Kettering Institute, uses the protein that causes progeria, a disorder of extreme premature aging, to successfully age neurons derived from iPS cells from Parkinson’s disease patients.

    Robert Lanza, a stem cell biologist at Advanced Cell Technology, takes another approach, aging cells by taking small amounts of mature neurons and growing them up in a new dish. “Each time you do this, you are forcing the cells to divide,” Lanza says. “And cells can only divide so many times before they reach senescence and die.” This process, Lanza believes, will mimic aging. He has also been experimenting with stressing the cells to promote premature aging.

    All of these techniques, Livesey believes, will allow scientists to study which aspects of the aging process—such as number of cell divisions and different types of environmental stressors—affect neurodegenerative diseases and how they do so. Adding to the complexity of the experimental system will improve the results that come out at the end. “You can only capture as much biology in iPS cells as you plug into it in the beginning,” Livesey says.

    But as Isacson and Loring’s work, has shown, even very young cells can show hallmarks of neurodegenerative diseases. “If a disease has a genetic cause, if there’s an actual change in DNA, you should be able to find something in those iPS cells that is different,” Loring says.

    For these experiments and others, scientists have been relying on iPS cells derived from individuals with hereditary or familial forms of neurodegenerative disease. These individuals, however, only represent about 5–15% of individuals with neurodegenerative disease; the vast majority of neurodegenerative diseases is sporadic and has no known genetic cause. Scientists believe that environmental factors may play a much larger role in the onset of these forms of neurodegenerative disease.

    That heterogeneity means it’s not yet clear whether the iPS cells from individuals with hereditary forms of disease are a good model for what happens in sporadic disease. Although the resulting symptoms may be the same, different forms of disease may use the same biological pathways to end up in the same place. Isacson is in the process of identifying the range of genes and proteins that are altered in iPS cells that carry Parkinson’s disease mutations. He intends to determine whether any of these pathways are also disturbed in sporadically occurring Parkinson’s disease to pinpoint any similarities in both forms of disease.

    Livesey’s lab just received a large grant to study people with an early onset, sporadic form of Alzheimer’s. “Although sporadic Alzheimer’s disease isn’t caused by a mutation in a single gene, the condition is still strongly heritable. The environment, obviously, has an important role, but so does genetics,” Livesey says.

    Because the disease starts earlier in these individuals, researchers believe that it has a larger genetic link than other forms of sporadic Alzheimer’s disease, which will make it easier to identify any genetic or biological abnormalities. Livesey hopes that bridging sporadic and hereditary forms of Alzheimer’s disease will allow researchers to reach stronger conclusions using iPS cells.

    Though it will be years before any new drugs come out of Livesey’s stem cell studies—or any other stem cell study for that matter—the technology has nonetheless allowed scientists to refine their understanding of these and other diseases. And, scientists believe, this is just the start. “There are an endless series of discoveries that can be made in the next few decades,” Isacson says.

    Image credit: Ole Isacson, McLean Hospital and Harvard Medical School/NINDS

    See the full article here.

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  • richardmitnick 6:24 pm on March 23, 2015 Permalink | Reply
    Tags: , high-intensity focused ultrasound therapy, Medicine   

    From New Scientist: “Ultrasound killed the surgical star” 2014 But Valuable 


    New Scientist

    06 January 2014
    Helen Thomson

    From brain to prostate, focused waves of sound can reach places a scalpel can’t, putting us on the brink of a surgical shake-up.
    (Image: Patrick George)

    PHYLLIS is having brain surgery. But she is wide awake. There are no scalpels and no blood, sliced flesh or bone in sight. Instead, the surgeon carefully places a cap on top of Phyllis’s head and flicks a switch. Deep inside her brain, a tiny region of tissue heats up and begins to burn, while surrounding brain cells are left unscathed. Later that day, Phyllis is able to go home, free from the neurological disorder that for the past 30 years has made her right hand tremble violently whenever she tried to use it.

    She has a form of ultrasound to thank for her remarkable recovery. Just as the sun’s rays can be focused by a magnifying glass to burn a piece of paper, high-intensity ultrasound waves can be concentrated to burn human tissue. The waves are harmless until they converge at the focal point, so a surgeon can operate deep inside the body without harming the surrounding tissue.

    This high-intensity focused ultrasound (HIFU) requires no cuts to be made, and many operations don’t even need an anaesthetic, so the patient can be in and out of hospital within a day. “When you’re dealing with a lot of very sick people, that’s a huge advantage,” says Gail ter Haar, who studies ultrasound at the Institute of Cancer Research in London.

    After promising trials treating prostate cancer, it is now looking as if HIFU could become a medical Swiss army knife for all kinds of procedures. And even in parts of the body where the focused waves can’t burn away tissue directly, they can still boost the uptake of drugs in specific organs. The method has even been used to prevent severe illness in fetuses in the womb.

    Phyllis’s success story is the latest step of a journey that began 70 years ago. John Lynn and his colleagues at Columbia University in New York were the first to try targeting ultrasound waves to destroy biological tissue, in the 1940s. Although they managed to create lesions in cat brains with minimal disruption to non-targeted areas, the need for a craniotomy – in which a bone flap is removed from the skull – together with a lack of sophisticated imaging technologies, meant there was limited interest in the technology for general surgery. Now, with more advanced transmitters that can focus beams behind hard tissue like bone, and imaging technology such as MRI, doctors can operate more accurately, targeting areas of tissue sometimes just fractions of a millimetre across.

    That precision looks set to revolutionise the treatment of prostate cancer. Conventionally, when tumours need to be eliminated, the entire prostate is removed, which can damage nerves and the muscles that control the ability to relieve yourself on demand. The result is that 70 per cent of patients lose the ability to get erections, and about 15 per cent become incontinent. A less-invasive option is radiotherapy, but it can still cause some damage to surrounding nerves. What’s more, radiotherapy is unlikely to be repeated if the cancer returns, because the risk becomes too great that DNA damage from the radiation will cause secondary tumours.

    With focused ultrasound, however, surgeons can burn away tumours bit by bit, targetting areas the size of a grain of rice (see “No blood, sweat or tears”). Trial results so far have been impressive: in a 2012 study of about 40 men receiving HIFU, 90 per cent could maintain an erection by the end of the study, and no man was left incontinent. One year later, 95 per cent showed no signs of the disease (Lancet Oncology, vol 13, p 622).

    The recovery times are particularly notable. “We’ve had some people who’ve said they’ve been shopping the same day as the procedure,” says Louise Dickinson at University College London, who is investigating the long-term outcomes of using the therapy for prostate cancer. “One man said it was easier than going to the dentist for a filling.” Widespread clinical trials of ultrasound treatment for prostate cancer are now under way, but further evidence of its long-term effectiveness will be needed before it is a recommended treatment.

    Buoyed by the promising results for prostate cancer, a range of trials are now investigating using sound to treat other disorders, including pancreatic cancer and lumps that form in the thyroid gland that can lead to cancer. One of the more ambitious ideas is to use HIFU to tackle problems deep in the brain. The technique has huge advantages, not least because you avoid cracking into the skull. What’s more, you can bypass the healthy layers of brain, preserving normal functions.

    That’s not to say it is simple. The rate at which ultrasound passes through different tissue types varies – bone absorbs a lot of sound, whereas the jelly-like tissue of the brain takes in much less. To make matters worse, our skulls are not a uniform thickness all the way around. So surgeons have to use CAT scans to measure the bone density at thousands of points around the scalp. Later, a cap full of ultrasound emitters, called transducers, will be placed on the patient’s head. Each transducer is tuned using information about the bone density underneath so that it emits just the right frequency, for just the right amount of time, to focus the waves at the desired point in the brain.

    Last year, the technique was used to treat 15 people with essential tremor, Phyllis among them (New England Journal of Medicine, vol 369, p 640). To do so, the doctors singed a tiny area of the thalamus that relays motor signals to the cortex – thus blocking some of the abnormal neuronal activity that would otherwise be transmitted to the muscles and cause shaking. “The whole procedure probably took less than 2 hours, and apart from a strange buzzing sensation, it was completely painless,” says Phyllis. Because the trial was designed to test the safety of the procedure, they only aimed to treat the movements in her right hand. The results were immediate. “As soon as I came out of hospital, my handwriting was perfect, like it used to be,” she says. “It’s got a little worse over time but it’s so much better than my left hand.” The other 14 patients in the trial experienced similar improvements, and although side effects included temporary problems with speech, and for four patients, minor but persistent alterations to sensations in their face or fingers, all agreed that it significantly improved their quality of life.

    The hope is that we might be on the cusp of a new wave of non-invasive brain surgery. “Soon, we’ll be starting a trial that will attempt to reduce movement problems in Parkinson’s and treat brain tumours,” says Neal Kassell, director of the Focused Ultrasound Foundation in Charlottesville, Virginia.

    Despite these successes, HIFU has its limitations. Bone cancer, for instance, is almost untouchable, because skeletal tissue quickly absorbs the ultrasound waves. “It’s hard to get any energy deep into the bone,” says Wladyslaw Gedroyc, a consultant radiologist at St Mary’s Hospital in London. Conventional surgery, too, struggles to remove this kind of cancer, because it is difficult to bypass vital nerves, and any bone that is removed has to be reconstructed with a graft or prosthesis.
    Bursting bubbles

    Focused ultrasound may be much more than a replacement for the scalpel, however. It could open doors to procedures that would be impossible by conventional methods. Of particular interest is using ultrasound to direct the delivery of drugs. One approach would be to create medicines that are injected in an inert form, and then activated near to a tumour using heat from HIFU. The idea is to boost the dose where it is most needed while reducing side effects in the rest of the body.

    In other instances, the treatment could be aided by “microbubbles”. This phenomenon was discovered by accident, or so the legend goes, says Eleanor Stride at the University of Oxford. “They used to be made just by shaking blood about and putting it back in.” Now, you can buy ready-made microbubbles that are between 1 and 10 micrometres across. They are comprised of a bubble filled with gas, supported by an outer shell made of lipids, proteins or polymers. The bubbles are often used during ultrasound scans, since they increase the contrast of the blood supply compared with the surrounding tissue. Once they are placed in the path of an ultrasound wave of the right frequency and intensity, however, they expand and contract until they suddenly collapse, creating a shockwave.

    Do this in the brain, and you could perforate the blood-brain barrier – the layer of membranes around capillaries that separate the blood from the extracellular fluid that flows around the brain. This barrier makes it difficult to deliver drugs into the brain during chemotherapy, for instance – but puncturing it is a tricky procedure, because permanent damage would weaken the brain’s defences against bacteria. A 2012 study in macaques, however, identified the specific frequency necessary to induce a reversible disruption to this barrier for just a few hours – enough time to allow drugs to be delivered to the brain with a minimal risk of infection (PLoS One, doi.org/p9n).

    Elsewhere in the body, it might be possible to place traditional chemotherapy agents into microbubbles and direct their implosion at the site you want destroyed. “It’s not been done yet, but we’re getting very close,” says Stride. Her colleague Constantin Coussios is about to take the first step. This year, his team will inject a chemotherapy drug into people with liver cancer. The drug will be encased in a lipid wrapper that can be broken down using ultrasound. If that works, they will then try to use microbubbles, filled with gas and the drug, as a vehicle – with the added advantage that the shockwave of the imploding bubbles would drive its chemical load deeper into the tumour, where it can do more damage. A similar approach would be particularly useful to push drugs into the bone cancers that are so difficult to reach with traditional surgery.

    Focused sound can even help doctors to treat patients at times when they were thought to be untouchable – such as when they are still in the womb. This was demonstrated for the first time in 2013, with a condition known as “twin reversed arterial perfusion”. This rare disorder involves two fetuses – one of which develops normally, while the other fails to develop a head, arms or heart. The two fetuses are connected by an umbilical cord that passes through the placenta, and the twin without a heart relies on blood pumped from its twin to stay alive. As a result, the healthy twin has to work extra hard to sustain both, which often results in heart failure and death.

    Surgeons used HIFU, between 13 and 17 weeks after conception, to sever the abnormal fetus from the placenta and release the healthy twin of this burden. The baby boy was later delivered successfully (Ultrasound in Obstetrics & Gynecology, vol 42, p 112).

    The success of such a delicate procedure offers a glimpse of what the future might hold. Kassell, for one, is sure that we are only just beginning to understand the potential of this technology. “It’s a stick that we’re still working out how to wield,” he says.

    Gedroyc agrees. “You have here a very powerful tool,” he says. “Once you start thinking about it, you’re really only limited by how imaginative you are.”

    This article appeared in print under the headline “Surgery’s new sound”

    See the full article here.

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